2025 was a strong year for www.MitoWorld.org. As an information, publishing, and community web hub devoted to mainstreaming mitochondria, mtDNA, and the mitonuclear system as core to physiology, medicine, health, and translational research, we now have positive user reactions and acceptance across the research, clinical, and patient worlds. Thank you to our visitors, readers, and followers on social media for this.
MitoWorld is a largely volunteer organization that succeeds due to the incredible support of our Scientific Advisory Board (SAB) and the efforts of Alex Sercel, PhD (MitoWorld Director of Scientific Affairs and cofounder), Gary Howard, PhD, (MitoWorld Editor-Writer), Dane Wolf, PhD (MitoWorld Microscopist, Writer), Kyrie Wilson, PhD (MitoWorld Director of Scientific Communications) and Zach Kirshner for his never-ending creativity in designing and managing the MitoWorld website.
We hope we are providing a constant drumbeat of attention for the emerging and ever more popular field of mitochondrial medicine and research, sharing key insights within the research, medical, and patient communities, and playing a unique role in advocating for deeper basic science for all things mitochondrial and mitonuclear.
As the publisher of MitoWorld and the founder of the parent nonprofit, www.NLET.org/biomed, my introduction, as a nonscientist, to mitochondria was first as a patient with a non-mutational mitochondrial dysfunction. This led me directly and personally into the vast and complex terra incognita of mitochondrial cellular biology, endosymbiosis, mtDNA, and its relationship to the nucleus. Having worked in big-science reporting and outreach in astrophysics and cosmology, I found biology more complicated, with less theory and a smaller emphasis on building basic science.
Report for 2025
MitoWorld launched in the spring of 2023 after early contact with Mike Murphy (Cambridge) and Phillip West (then Texas A&M Hospital, now the Jackson Laboratory), which led to support from Navdeep Chandel (Northwestern) and Anu Wartiovaara (University of Helsinki), resulting in the formation of our SAB with the support of Douglas Wallace (CHOP) and others.
www.MitoWorld.org (web hub, communications, and media) and www.MITOS.Global (collaboration network structure) are sub-parts of the California-based research and development human capital and STEM nonprofit National Laboratory for Education Transformation, www.NLET.org, founded in 2011 and based in Oakland, CA.
1. MitoWorld Media
At this stage, MitoWorld’s primary activity is publishing five or more MitoBlog posts every month reviewing top papers in the field, covering leading conferences, and occasionally producing long-form MitoCast podcasts.
MitoBlog Posts: 55 posts in 2025 in four categories: Mitochondrial Frontiers, From the Field, Profiles, Events. Examples: First Mito Drug Approval, Mitochondria In Space, José Antonio Enríquez Profile (CNIC, Madrid), Motherboard of the Cell (Scientific American), mtDNA FASBE Conference
MitoCast Podcasts: Conducted by Danny Levine of the www.LevineMediaGroup.com these include Douglas Wallace (CHOP), Navdeep Chandel (Northwestern), Craig Thompson (Memorial Sloan Kettering), Chris Mason (Weill Cornell) with Afshin Beheshti (U Pittsburgh) “Is Life in Space Possible.”
UMDF-MitoWorld “Beyond the Disease”: Each month MitoWorld provides the United Mitochondrial Disease Foundation, www.UMDF.org, a set of blogs and podcasts for their monthly newsletter.
What Mito Media Needs: MitoWorld, primarily a volunteer organization, is seeking volunteers or stipend-supported contributors to help expand Mito Media—curating research papers into collections, managing social media, curating articles, videos, and programs. Writers are also welcome.
Contact: info@mitoworld.org
2. MitoWorld Directories
MitoWorld provides two primary sets of registries or directories for “Patients and Clinics” and “Research and Industry.” These directories were created, based on my experience and that of many others, in trying to find resources, contacts, and pathways to understand and follow the research community, clinical options, and mitochondrial science more broadly.
We have only begun this work. In 2026, we aim to grow these directories and use AI to identify mitochondrial researchers and build comprehensive databases across clinics, patient organizations, research groups, industry, and funding entities.
What Mito Directories Needs:
MitoWorld seeks volunteer or stipend-supported coordinators to help secure funding and support to build out these registries, implement structured databases, and deliver deep search and discovery capabilities for the mitochondrial community. MitoWorld has an AI partnership that can assist with this work.
See: https://www.heurekalabs.co/
3. Introducing MITOS Global (Mitochondria, Informatics, Translation, Outreach, Science)
www.NLET.org/biomed, the nonprofit parent of MitoWorld, recognized that MitoWorld serves as an information, communication, and outreach hub, but it does not itself conduct research. MitoWorld exists to support, connect, and amplify the mitochondrial research, clinical, and patient communities.
Two key realities emerged:
- Funding is limited and fragmented, preventing sustained, coordinated investigation across labs and disciplines.
- There is insufficient time and infrastructure for collaborative, systems-level research integrating biology, computation, and data science.
MitoWorld repeatedly heard from researchers about the need for coordinated, multi-investigator efforts addressing foundational mitochondrial questions.
www.MITOS.Global was organized to meet this need, with leadership including Patrick Chinnery, MD, PhD (University of Cambridge, MRC-UKRI), Anu Suomalainen Wartiovaara, MD, PhD (University of Helsinki), Phillip West, PhD (The Jackson Laboratory), and Jared Rutter, PhD (University of Utah).
The parent nonprofit, www.NLET.org, has over 14 years of experience managing large-scale, multi-institutional collaborations supported by federal agencies and philanthropic organizations.
Currently, two collaborative, multi-PI projects are active within MITOS Global, with two more in development.
Human Mitochondrial Metabolic Drive and Ecological Consequences
Activity: Letter of Interest, Simons Collaboration in Ecology and Evolution, Simons Foundation
Principal and Co-Principal Investigators:
Florencia Camus, University College London
Iain Johnston, University of Bergen
Nick Jones, Imperial College London
Kevin McCann, University of Guelph
Dan Mishmar, Ben-Gurion University of the Negev
Joel Sharbrough, University of California, Santa Barbara
Gordon Freedman, National Laboratory for Education Transformation (Applicant/Lead)
Ken Sorey, National Laboratory for Education Transformation (Project Personnel)
Mitochondrial Intercellular Mobility: Standards, Methods, and Validity
Activity: Concept Letter Submission, ARIA Precision Mitochondria, Advanced Research and Invention Agency (UK)
Note: The ARIA category MITOS Global submission is on hold until initial research begins. However, the core MITOS team continues to advance mobility protocols.
Principal and Co-Principal Investigators:
Phillip West, PhD, The Jackson Laboratory
Rajarshi Mukherjee, FRCS, PhD, University of Liverpool
Martin Picard, PhD, Columbia University
Kostas Tokatlidis, PhD, University of Glasgow
Stephen P. Burr, PhD, University of Cambridge
Cristiane Benincá, PhD, UCLA
Matthew Hirschey, PhD, Duke University
Internal Team:
Alexander J. Sercel, PhD – Director of Scientific Affairs, www.MitoWorld.org
Colwyn Headley, PhD – Stanford University
Gavin McStay, PhD – Liverpool John Moores University
Dane M. Wolf, PhD – www.MitoWorld.org
Kyrie Wilson, PhD – Medical College of South Carolina
Yasemin Sancak, PhD – University of Washington
4. External Education Outreach
October 2025: STEM Magazine, “Welcome to Mitoverse,” by Dane Wolf, PhD, and Gordon Freedman. An in-depth introduction to mitochondria in a major STEM education publication reaching over 500,000 readers.
5. MitoWorld Conference Support
MitoWorld supports mitochondrial conferences as a media sponsor, typically exchanging coverage and promotion for participation. MitoWorld also submits posters describing its mission to expand awareness of mitochondrial science and engage future scientists.
- January 13–16, 2025 | Keystone Symposia: Mitochondrial Biology in Health and Disease | NTUH International Convention Center, Taipei, TPE, Taiwan. Scientific Organizers: Lena Pernas, Anne N Murphy, and Johan Auwerx. MitoWorld LinkedIn Post.
- March 23-28, 2025 | Gordon Research Conference: Mitochondria Metabolism and Signaling, Ventura, CA: Organizers: Giovanni Manfredi, Chair; Janine H Santos, Co-Chair; Maria Eugenia Soriano, Vice Chair; Jared P Rutter, Co-Vice Chair. MitoWorld Support Logo. MitoWorld Poster.
- April 27-29, 2025 | Northwell Health & Feinstein Institute: Mitochondrial Transplantation and Next Generation Therapeutics Conference, Hofstra University. Organizer: Lance Becker. MitoWorld was a co-organizer. MitoWorld Poster.
- June 1-5, 2025 | FASEB: Mechanisms of Mitochondrial DNA Mutation and Repair, Nashville, TN. Organizers: Primary Organizer, Patrick Chinnery; Organizers, Michal Minczuk, Agnel Sfeir. MitoWorld, Essential Sponsor. MitoWorld Poster. MitoBlog Post. MitoWorld LinkedIn Post.
- June 18-20, 2025 | The UMDF Mitochondrial Medicine for Scientists and Clinicians Mitochondrial Medicine 2025, Clinical & Scientific Program 2025. St. Louis, MO. Organizer: Jonathan Brestoff. MitoWorld Poster. MitoBlog Post. MitoWorld LinkedIn Post.
- July 14-15, 2025 | Van Andel Institute, Science on the Grand. MitoWorld was a sponsor, STEM educators.
- December 12, 2025 | Columbia University, Mitochondria PsychoBiology Lab: Mitochondrial Stress, Brain Imaging, and Epigenetics Symposium, Columbia University, NY: Organizer Martin Picard. MitoBlog Post. MitoWorld LinkedIn Post.
Long associated only with energy and somewhat ignored, mitochondria are now recognized as key components in development and disease. On December 12, nearly 550 researchers met in person and virtually at Columbia University to assess the accomplishments and future directions of the Mitochondrial Stress, Brain Imaging, and Epigenetics—MiSBIE study. The study (Kelly et al. 2024) sought to understand the role of mitochondria and energy in mind-body processes and mitochondrial diseases. The “mother paper” (Kelly et al.), as they call it, also spawned other papers.
Symposium organizer Martin Picard (professor of behavioral medicine, Columbia) began by describing the holistic approach to the study. “We want to understand you as a person,” they emphasized to each study participant, as they welcomed them for the 2-day protocol in Manhattan.
Humans can be studied at various levels, including the molecular, cellular, tissue and organ, individual, and populations. The study sought to elucidate the interconnections of these levels through the lens of energy. More specifically, the MiSBIE team focused on the interactions of the immune system, mitochondria, the brain and nervous system, stress hormones, cognition, and behavior. Picard emphasized the importance of working as a team by noting the adage, “If you want to go quickly, go alone. If you want to go far, go together.” The discussions that followed featured several of his research group who contributed to the study.
Brain Mitochondria: The Energetic Landscape
In parallel with integrating mitochondrial energetics with psychobiology, the team developed the first mitochondrial map of the brain (Mosharov et al., 2025), a process led and described by Michel Thiebaut de Schotten (director of research, NeuroCampus of the University of Bordeaux). To link cognitive neuroscience and cell biology, they divided a frozen human coronal hemisphere section into 703 cubes or voxels (3 × 3 × 3 mm). Then, they defined the mitochondrial phenotypes (e.g., oxidative phosphorylation (OxPhos) enzyme activities, mitochondrial (mt)DNA and volume density, and mitochondria-specific respiratory capacity) in each voxel. The map revealed different characteristics for each region of the brain. If validated, the MitoBrainMap v1.0 of mitochondrial phenotypes might eventually allow exploration of the energetic landscape of normal brain function and correlations with standard neuroimaging methods—by magnetic resonance imaging (MRI).
“If this works, it would really be game changing,” said Picard. “You beam energy at the brain with a big magnet, then capture energy coming out of the brain, and somehow that tells you something about the biology of mitochondria. Amazing if this works.”
Building on the MiSBIE neuroimaging dataset, Tor Wager, PhD (professor of neuroscience, Dartmouth) and postdoctoral fellow Ke Bo examined behavioral and cognitive tasks through an energy-focused lens. One of their goals was to identify useful brain neurologic signatures associated with mitochondrial disorders. The molecules GDF15 and FGF21 show the strongest differences between individuals with mitochondrial disorders and controls. Wager used fMRI imaging to look for patterns in response to different tasks. These include cognitive (working memory, executive function tests), affective (cold pain), and sensory (multisensory with lights and stresses). Some of the correlations to mitochondrial disorders include sensitivity to negative emotions, but not to heat. In summary, the team finds that some brain functions and neural circuits are selectively vulnerable to energy deficits (Bo et al. Biorxiv 2025), consistent with an energy tradeoffs or “triage” model of psychopathology.
Immune Cell Bioenergetics
The group then wanted to examine the bioenergetics of immune cells. Jack Devine described how they stratified the phenotypes (or mitotypes) of immune cells. He used a new method developed by Anna Monzel, called mitotyping. Using principal component analysis, hierarchical clustering, and downstream analysis, they analyzed single immune cells from 164 people (ages 26–84). The MiSBIE team found that different types of immune cells have distinct patterns of activity (e.g., OxPhos, glycolysis) and aging.
To measure the bioenergetics of those cells from individuals with mitochondrial disorders, the group used extracellular flux analysis (Seahorse). Anna Monzel explained the process in beautiful details. The MiSBIE team isolated blood cells—monocytes, lymphocytes, neutrophils, platelets—from fasting individuals. For each cell type, they then measured their oxygen consumption and extracellular acidification rates to estimate OxPhos and glycolytic activities, using drugs that block specific enzymes in the mitochondria. OxPhos capacity was reduced in some cell types (not all) in people with mitochondrial disorders, but glycolysis was largely unchanged.
Using a biochemical approach called the mitochondrial respiratory capacity (MRC, formerly the Mitochondrial Health Index, MHI), Cynthis Liu examine mitochondrial biology in the same cells, of the same MiSBIE participants. She then used these data to explore the psychobiological relationships of immune cell mitochondria and mood symptoms, including anxiety and depressive symptoms. The work focused on mitochondrial respiratory chain at complexes I, II and IV, citrate synthase, and mtDNA content. The conclusion was that the maximal energetic capacity of immune cells is largely intact in mitochondrial diseases. Immune mitochondria are thus unlikely to reflect mitochondrial energetics in other tissues, such as the brain, muscles, and other organs.
Health Indicators: Time Perception
The MiSBIE study then focused on the indicators of health for those with mitochondrial disease. Two of these are the perception of time and allostatic load. Darshana Kapri examined the relationship of mitochondria to time perception. Individuals perceive time differently. Some people’s internal clocks run faster or slower than the actual time. Mitochondrial disorders didn’t directly affect time perception (faster or slower) but seemed to affect how potential drivers of time perception, including stress/metabolic hormones, such as norepinephrine, or metabolic rate. The team also discovered potentially meaningful associations between symptoms of burnout and fatigue and time perception, which demand validation in future studies.
Alex Junker then looked at allostatic load—a multi-system metric of physiological dysregulation known to predispose to disease. Allostatic load was higher in people with mitochondrial diseases and strongly correlated with lifetime stress and trauma. So genetics is important, but those with disease might be affected by their lived environment and the psychosocial factors that surround them. This new knowledge could motivate interventions or approaches that can provide additional support for those who have mitochondrial diseases.
Energetics of Stress: Cell-Free Mitochondria
The study also focused on the energetics of stress. Natalia Bobba-Alves described how the group developed a stress reactivity protocol and the effects of mitochondrial disorders. That protocol, which included eight concurrent blood and saliva collection timepoints over a 2-hour period, was used to study several stress mediators. The main stressor was a 5-minute speech task where participants had to give a speech in front of a white coat-wearing intimidating evaluators, while being (mock) videotaped.
David Shire explained their work on cell-free mtDNA in saliva and blood and stress. Levels of cell-free mtDNA are elevated in patients with cancer, heart disease, and inflammation. Higher levels of cf-mtDNA were detected in saliva than in serum or plasma from the same person. Stress caused a nearly 10-fold elevation in saliva cf-mtDNA within 10 minutes on average.
Mangesh Kurade presented results on FGF21 levels after the same stressor. The levels are significantly elevated in people with mitochondrial disorders. They decrease from morning to afternoon, and tend to be higher in people with higher body fat and in older people. Mental stress decreased plasma FGF21 in most control individuals, whereas it caused a robust increase in people with mitochondrial disorders—a remarkable divergence.
Caroline Trumpff looked at whether mental stress altered the mitochondrial disease biomarker GDF15. This molecule is the most robust available marker of mitochondrial disorders and energetic stress. The MiSBIE team found that psychological stress alone is sufficient to causes GDF15 levels to rise, both in blood and in saliva. This new discovery links mental and energetic stress, suggesting that both might converge on mitochondria and reductive stress, the key trigger for GDF15 release.
Future Directions: Hypermetabolism and mtDNA Instability
Evan Shaulson covered an ambitious follow up study: the Mitochondrial Daily Energy Expenditure (MDEE) study. Individuals with OxPhos defects often have fatigue and a short lifespan—on average reduced by 3-4 decades. Evan Shaulson described in vitro experiments from Gabriel Sturm on patient-derived fibroblasts, where subjecting cells to conditions that disrupted OxPhos doubled cellular energy expenditures. This state of hypermetabolism was associated with mtDNA instability, activation of the integrated stress response, and secretion of age-related cytokines and metabokines.
In the new MDEE study (manuscript in preparation), additional experiments were conducted with volunteers who spent a day in a small room while their metabolic rates, activity levels, and other psychobiological parameters were carefully and continuously measured. Half of the volunteers had a mitochondrial disease, and the other half were healthy controls—as in MiSBIE. For a further 8 days, MDEE participants lived their normal lives. The study found that like the fibroblast experiments, individuals living with OxPhos defects experience hypermetabolism. Thus, in both isolated cells and people, mitochondria with defects result in hypermetabolism and reduced lifespan, the connection between which remains to be better understood. This may relate, as the team proposes, to energy constraints that force deleterious tradeoffs where stress-related processes compete with health and healing-promoting processes.
Martin Picard summed up the symposium by focusing on a major gap in knowledge: “Healing is a set of dynamic, energetic processes by which an organism moves towards optimal function. Healing involves growth and development, recovery from injury, and adaptation that increase coherence and efficiency across the organism. Although healing is most likely the key driver of health, and the basis for not getting sick in the first place, we don’t have a science of this. We need a science of healing,” he said, pointing to their work around the science of health, and a new initiative to be unveiled in the coming year.
“Rational, scientific ways to harness the healing process would likely lead to new treatments and interventions that help optimize mitochondrial energy transformation. That would likely then contribute to more coherent and efficient psychobiological processes, freeing up energy to fuel the healing process and sustain health across the lifespan.”
The MiSBIE Symposium concluded with a reception that celebrated the scientific success of the NIH-funded study, supported by Baszucki Group. “MiSBIE sets the table for a new phase in the evolution of health sciences. Understanding psychobiological processes at an energetic level provides a foundation to develop a true science of healing: Healing Science,” said Picard. “There is a lot to be excited about. And we need everyone on board, not just scientists, to come along and join the movement.”
References
Kelly C, Trumpff C, Acosta C, Assuras S, Baker J, Basarrate S, Behnke A, Bo K, Bobba-Alves N, Champagne FA, Conklin Q, Cross M, De Jager P, Engelstad K, Epel E, Franklin SG, Hirano M, Huang Q, Junker A, Juster R-P, Kapri D, Kirschbaum C, Kurade M, Lauriola V, Li S, Liu CC, Liu G, McEwen B, McGill MA, McIntyre K, Monzel AS, Michelson J, Prather AA, Puterman E, Rosales XQ, Shapiro PA, Ghire D, Slavich GM, Sloan RP, Smith JLM, Spann M, Spicer J, Sturm G, Tepler S, Thiebaut de Schotten M, Wager TD, Picard M, The MiSBIE Study Group (2024) A platform to map the mind–mitochondria connection and the hallmarks of psychobiology: The MiSBIE study. Trends in Endocrinology & Metabolism (10): 884–901.
Mosharov EV, Rosenberg AM, Monzel AS, Osto CA, Stiles L, Rosoklija GB, Dwork AJ, Bindra S, Junker A, Zhang Y, Fujita M, Mariani MB, Bakalian M, Sulzer D, De Jager PL, Menon V, Shirihai OS, Mann JJ, Underwood M, Boldrini M, Thiebaut de Schotten M, Picard M (2025) A human brain map of mitochondrial respiratory capacity and diversity. Nature 641: 749–758.
Sturm G, Karan KR, Monzel AS, Santhanam B, Taivassalo T, Bris C, Ware SA, Cross M, Towheed A, Higgins-Chen A, McManus MJ, Cardenas A, Lin J, Epel ES, Rahman S, Vissing J, Grassi B, Levine M, Horvath S, Haller RG, Lenaers G, Wallace DC, St-Onge M-P, Tavazoie S, Procaccio V, Kaufman BA, Seifert EL, Hirano M, Picard M (2023) OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases. Communications Biology 6(1): 22.
https://www.nature.com/articles/s42003-022-04303-x.pdf
Recently, a multi-institute research team led by Yosuke Togashi reported on a study that showed that cancer cells transfer mitochondria with mutant DNA and inhibitory molecules to immune cells to reduce the antitumor response. This previously unknown mechanism also shows that cancer cells with mutated mitochondrial (mt) DNA indicate a poor prognosis for certain patients.
Cancers use many strategies to avoid immune surveillance. Among those are the acquisition of mitochondria from T cells that infiltrate the tumor. Those mitochondria enhance the cancer cells energy production. But the transfer of mitochondria also works in the other direction. Mitochondria with mutations from the cancer cells are transferred to the immune cells. Those defective organelles degrade the antitumor response. Thus, the metabolic reprogramming resulting from the bidirectional exchange of mitochondria creates an environment that encourages tumor growth.
The Togashi research team sought to determine the mechanisms that promote that exchange. They examined clinical samples of immune cells for mtDNA mutations from the cancer cells. They found similar mutations in mtDNA in the immune cells. In most cases, mitochondria with mutated mtDNA are destroyed by mitophagy. However, the team identified proteins that attach to the mitochondria with mutated mtDNA and are transferred with them to the immune cells. One of these was the mitophagy-inhibiting protein USP30. Those recipient immune cells then failed to undergo mitophagy. In addition, the T cells with the mutant mitochondria became senescent.
This work has valuable clinical implications. Finding of mutant mtDNA in the cancer cells indicates that immune checkpoint inhibitors may be less effective in patients with melanoma and non-small-cell lung cancer.
A conversation with Dr. Togashi
MitoWorld: What directions do you foresee your research taking to advance this work?
Togashi: Our next steps are to clarify the mechanistic basis of mitochondrial replacement in addition to just transfer, the key molecules on donor and recipient cells, and the tumor microenvironmental conditions that promote it. We will then expand the work across additional cancer types and other recipient cell populations (beyond T cells) to build a broader map of who transfers mitochondria to whom and with what functional consequences. We are also interested in whether similar mitochondrial transfer in non-cancer diseases, such as chronic inflammation disease. In parallel, we will determine how transfer intersects with mitochondrial dynamics (fusion-fission, mitophagy, and quality control) that may determine whether transferred mitochondria persist. Ultimately, we aim to translate these findings into biomarkers that predict therapy response and therapeutic strategies that restore mitochondrial quality control to improve immunotherapy efficacy.
MitoWorld: Do you have any thoughts on the mechanism by which the immune cells receiving the mutated mtDNA become senescent?
Togashi: We think senescence is likely driven by a combination of mitochondrial dysfunction and stress signaling. Mutant mitochondria can impair respiratory capacity and elevate reactive oxygen species, which may trigger DNA-damage responses and activate pathways, such as p53–p21 and/or p16. Importantly, if mitophagy is suppressed, these damaged organelles may persist, making the dysfunction more durable.
MitoWorld: As you noted, mitochondria might be mediated by various mechanisms. Do you have a favorite candidate for this process?
Togashi: Several mechanisms could plausibly mediate mitochondrial transfer, including tunneling nanotubes, extracellular vesicles, and direct cell-cell contact-dependent processes. From our observations so far, a leading candidate is tunneling nanotubes and/or EVs. At the same time, we have the impression that the dominant route may differ, depending on the cell type and context. So these mechanisms are not mutually exclusive and may operate in parallel in different tumor microenvironments.
MitoWorld: Your work here and that of others have provided good evidence for the concept of mitochondrial transfer. However, some researchers have been slow to warm to this idea. Can you speculate on why there has been this reluctance to accept this?
Togashi: I think the hesitation is understandable. Demonstrating mitochondrial transfer convincingly in vivo is technically challenging: mitochondria are abundant, dynamic, and easy to mis-attribute due to imaging limitations, labeling artifacts, or contamination during cell isolation. In addition, the field has long emphasized mitochondria as strictly cell-autonomous organelles, so the conceptual shift takes time. In our case, we view the evidence as particularly strong because we can identify transferred mitochondria by shared genetic mutations in both clinical specimens and in vivo models, providing an orthogonal line of support beyond imaging alone. As methods improve, particularly lineage tracing, spatial approaches, and rigorous controls, I expect the evidence base will continue to strengthen and the community will converge.
MitoWorld: Do you have any speculation on how your findings might be translated to clinical applications?
Togashi: We see a few translational opportunities. First, tumor mtDNA mutation profiles could serve as biomarkers to stratify patients who are less likely to benefit from immune checkpoint inhibitors and, thus, help to guide treatment selection. Second, therapeutically targeting the transfer process or restoring mitochondrial quality control in recipient immune cells may help to preserve anti-tumor immunity. Third, these insights may inform combination strategies (e.g., pairing immunotherapy with mitochondria-targeted agents), thereby converting non-responders into responders.
MitoWorld: How did you become interested in mitochondria?
Togashi: My original training is in pulmonary medicine and thoracic oncology. From there, I became increasingly interested in cancer immunology, and during my postdoctoral period, I worked primarily on regulatory T cells. I was already aware of the accumulating evidence that mitochondrial dysfunction is an important feature of exhausted T cells, but when I was preparing to start my own laboratory, I was searching for an original research direction. Around that time, I learned about the phenomenon of mitochondrial transfer, and it immediately struck me as a fascinating and potentially transformative concept for understanding tumor-immune interactions. That was the starting point that led me to pursue this line of work.
Reference
Ikeda H, Kawase K, Nishi T, Watanabe T, Takenaga K, Inozume T, Ishino T, Aki S, Lin J, Kawashima S, Nagasaki J, Ueda Y, Suzuki S, Makinoshima H, Itami M, Nakamura Y, Tatsumi Y, Suenaga Y, Morinaga T, Honobe-Tabuchi A, Ohnuma T, Kawamura T, Umeda Y, Nakamura Y, Togashi Y (2025) Immune evasion through mitochondrial transfer in the tumour microenvironment. Nature 638: 225-236.
A paper in Nature Cancer by a multi-institute research team, led by Michael Cangkrama and Sabine Werner at the ETH Zurich, describes how cancer cells use the transfer of mitochondria to highjack fibroblasts to support the cancer. The study also implicates a protein as critical for the transfer that may be useful in novel therapeutic strategies.
The transfer of mitochondria from various cell types into cancer cells has been reported to enhance cancer cell proliferation, motility and more. Fibroblasts associated with tumors are known to adopt certain characteristics, and they frequently support cancer development. The Cangkrama-Werner team sought to determine if the transfer of mitochondria might work in the opposite direction. In other words, do cancer cells transfer mitochondria to the fibroblasts?
To answer this question, the team examined cancer cells and fibroblasts in co-cultures and xenograft tumors. Intriguingly, mitochondria were transferred to the fibroblasts where they caused changes in the metabolism of the recipient cells. The fibroblasts began to express markers associated with cancer-associated fibroblasts and to release secreted soluble and extracellular matrix proteins that support tumor growth. The team also found that the transfer of mitochondria depends on the mitochondrial trafficking protein MIRO2. Without MIRO2, the transfer and the other changes failed. These findings are consistent with the overexpression of MIRO2 at the leading edge of epithelial skin cancers and other malignancies. Finally, they found that the mitochondria are transferred through thin membranous structures called tunneling nanotubes.
This study demonstrates that mitochondrial transfer from cancer cells to fibroblasts is a key regulator of CAF differentiation. The findings also implicate MIRO2 and mitochondrial transfer as potential targets for strategies to treat cancers.
A conversation with Drs. Cangkrama and Werner
MitoWorld: Can you give us an idea of what studies you might do to advance the findings presented here?
Werner: There are several open issues, including the signals that induce the transfer, the genes and proteins that promote the transfer and the targets of the transferred mitochondria, which induce the pro-tumorigenic phenotype in fibroblasts.
MitoWorld: You showed that oxidative phosphorylation is the main activity that is influenced by the mitochondrial transfers. Can you speculate on how that process translates into the changes in gene expression in the fibroblasts? Might there be other mitochondrial activities involved in activating the interferon-response genes?
Werner: Oxidative phosphorylation is highly relevant in this context, but it is probably not the only relevant factor. Oxidative phosphorylation results in the production of various metabolites, which are likely to regulate transcription factors that control gene expression in fibroblasts. We found that the interferon-response genes are not regulated by transferred mitochondria, but likely by transfer of other molecules from cancer cells to fibroblasts in co-cultures, which remain to be identified.
MitoWorld: The transfer of mitochondria from cell to cell has been somewhat controversial. Can you comment on the seeming reluctance of some researchers to embrace this concept?
Werner: Many results were obtained with MitoTracker, which is known to be leaky. Several studies did not include appropriate controls to address this problem, which might have contributed to skepticism about mitochondrial transfer. The concept was also unexpected when first proposed. Even when transfer occurs, it is difficult to predict and appears to depend on specific conditions, such as cellular stress or high metabolic demand, further fueling doubts about its physiological relevance. However, many exciting and well-controlled studies have recently been published, which show the relevance of mitochondrial transfer under various conditions. This makes mitochondrial transfer a promising area of research, with the potential to uncover new mechanisms of intercellular communication and to develop innovative therapeutic strategies.
MitoWorld: Can you speculate how your findings might translate to therapies for cancer?
Werner: There is a long way from this discovery to a cancer drug. Nevertheless, our work suggests that inhibition of mitochondrial transfer (e.g., by blocking MIRO2 or other proteins important for the transfer) could be a novel approach for cancer treatment. In addition, identification of the relevant targets of the mitochondrial transfer in recipient fibroblasts could provide new therapeutic opportunities.
MitoWorld: How did you first become interested in mitochondria?
Werner: Several previous studies of our laboratory revealed the important role of mitochondria in the pro-tumorigenic cancer-associated fibroblast phenotype. This raised our interest in these exciting organelles.
Reference
Cangkrama M, Liu H, Wu X, Yates J, Whipman J, Gäbelein CG, Matsushita M, Ferrarese L, Sander S, Castro-Giner F, Asawa S, Sznurkowska MK, Kopf M, Dengjel J, Boeva V, Aceto N, Vorholt JA, Werner S (2025) MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation. Nature Cancer 6: 1714–1733.
Recently, a multi-institute team led by Thomas Langer, PhD, at the Max-Planck-Institute for Biology of Ageing examined the effects on ribonucleotide incorporation into mitochondrial (mt)DNA on inflammation. Published in Nature, the study found that increased incorporation of ribonucleotides into mtDNA during replication resulted in the release of mtDNA fragments into the cytosol and an increase in inflammation.
Mitochondria are now recognized as far more than just producers of ATP. They have many critical activities, and disruption of those functions is associated with inflammation, cell death, and disease. Dr. Langer´s team previously showed that disturbances in the nucleotide metabolism result in the release of mtDNA into the cytosol and, like pathogenic DNA, the mtDNA elicits an inflammatory response by the cell. Now they found that this is caused by an increased incorporation of ribonucleotides into mtDNA. The incorporation of ribonucleotides is a problem for mitochondria because they lack the enzyme that removes those molecules from DNA.
More specifically, they looked at mice that lacked MGME1, a mitochondrial exonuclease that maintains mtDNA, and observed increased ribonucleotide incorporation into mtDNA. Similarly, cells lacking the mitochondrial protease YME1L or senescent cells that have decreased deoxynucleotide levels accumulate ribonucleotides in their mtDNA. As a result, mtDNA leaks into the cytosol, and induces an inflammatory senescence-associated secretory phenotype, which can be reduced by adding deoxyribonucleosides.
Based on these findings, they conclude that throwing nucleotide metabolism out of balance leads to incorporation of ribonucleotides into mtDNA and age- and mtDNA-dependent inflammatory responses and SASP in senescence. The study results provide clues to several diseases, such as renal failure, systemic lupus erythematosus, cancers, and neurodegenerative diseases
A Conversation with Dr. Langer
MitoWorld: What are the likely next steps to continue this research?
Langer: This work can be taken in many different directions. Since we observe the incorporation of ribonucleotides into mtDNA in aged tissues and in senescent cells, it will be of interest to better understand the relevance of this phenomenon for the increased chronic inflammation with age. Which cells are predominantly affected and vulnerable to metabolic disturbances inducing mtDNA-dependent inflammation? From a mechanistic angle, we would like to understand better how replication stress ultimately lead to the release of mtDNA into the cytosol.
MitoWorld: Detection of double-stranded DNAs in the cytosol is a key feature of the innate immune system, but the leaking mtDNA fragments in senescent cells seems to be an “oversight” of evolution. Is this another example of the problems we face with living longer now?
Langer: The accumulation of ribonucleotides in mtDNA in aged tissues may indeed suggest that this problem worsens with age and, in this sense, it may contribute to problems associated with long life. However, we should keep in mind that mtDNA-driven inflammation is not necessarily always bad, as it was shown previously in models for mitochondrial disease that low rates of mtDNA release can prime cells and tissues to better respond to viral inflammation.
MitoWorld: Your finding that mtDNA fragments accumulate in senescent cells is intriguing, especially given that so many diseases of aging (especially neurodegenerative disease) feature inflammation. Could you expand on that idea?
Langer: A cell-cycle arrest and inhibition of nuclear DNA replication is a hallmark of senescent cells that therefore reduce the synthesis of deoxynucleotides, the building blocks of DNA. However, mtDNA replication still occurs in senescent cells (i.e., in the presence of low deoxynucleotide levels). This leads to increased ribonucleotide incorporation into mtDNA and inflammatory SASP. Indeed, this response is detrimental in many diseases settings, stimulating intense efforts to identify senolytics to selectively remove senescent cells from tissues. Our findings suggest that rebalancing the nucleotide metabolism helps to suppress the SASP, which therefore might represent an alternative approach for the treatment of at least some aging associated diseases.
MitoWorld: Can you speculate on how your findings might be translated into potential treatments beyond simply treating the inflammation?
Langer: Although it remains speculative at this point, it is an attractive possibility to use deoxynucleoside therapy to restore the nucleotide balance and to alleviate inflammation in autoimmune diseases or in ageing. Just recently, the FDA has approved a nucleoside therapy for thymidine kinase 2 deficiency, a rare mitochondrial disorder affecting children.
MitoWorld: How did you come to be interested in mitochondria in the first place?
Langer: Mitochondria are in many ways fascinating organelles. They are dynamic and very heterogeneous in different cells and tissues, reflecting their diverse functions. I originally studied protein folding and turnover in bacteria and then got interested in mitochondrial proteins and only realized with time that these processes often drive adaptative responses of mitochondria that are so important to understand their role in aging and disease. The fascination never stops!
Reference
Bahat A, Milenkovic D, Cors E, Barnett M, Niftullayev S, Katsalifis A, Schwill M, Kirschner P, MacVicar T, Giavalisco P, Jenninger L, Clausen AR, Paupe V, Prudent J, Larsson N-J, Rogg M, Schell C, Muylaert O, Larsson E, Nolte H, Falkenberg M, Langer L (2025) Ribonucleotide incorporation into mitochondrial DNA drives inflammation. Nature 24: 1-9.
Unlike the nuclear genome, which contains genes from both parents, the mitochondrial genome is inherited only from the mother. This presents a problem since mitochondrial DNA (mtDNA) is prone to mutations that can accumulate over generations and threaten species survival. To avoid this, two still poorly understood mechanisms have been selected for in evolution to counteract the accumulation of harmful mtDNA mutations: the bottleneck, whereby only a small number of mtDNA molecules is passed on to the next generation and purifying selection, a mechanism that prevents mtDNA molecules with severe mutations from being transmitted.
A recent study published in Science Advances sought to better understand how these two mechanisms cooperate to ensure healthy mitochondria in offspring. The research was led by Professor Nils-Göran Larsson, MD, PhD, and performed at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet, Sweden. Dr Laura Kremer, first author of the study is currently an independent researcher at University of Göttingen and was conducting the research as a postdoc at Karolinska Institutet.
To explore the role of the bottleneck and purifying selection in the transmission of mutant mtDNA, the team produced mouse models with random mtDNA mutations along with alleles that modulated mtDNA levels or decreased autophagy.
They found that tightening the bottleneck, by decreasing the amount of mtDNA in the mother, resulted in greater variability in the levels of mtDNA mutations between individuals but reduced the overall mutational burden. Vice versa, decreasing autophagy weakened the selection, allowing more mutant mtDNA molecules to be passed on to the offspring leading to an increased mutation burden.
This study yielded novel insight by showing that the two mechanisms directly interact. Learning how cells protect the mitochondrial genome is valuable not only from an evolutionary perspective but also has medical relevance. Mutations in mtDNA are associated with many human diseases, including mitochondrial disorders, cancer, neurodegeneration, and ageing.
A conversation with Dr. Larsson
MitoWorld: You have a prolific laboratory, and this paper represents a great deal of work. Perhaps the work in this paper has progressed since its publication. Could you summarize the direction of any newer work?
Larsson: Since the publication, one direction we have undertaken involves the development of new mouse models that allows us to track different type of mtDNA variants and understand whether there are differences in the selective mechanisms that limit their transmission.
MitoWorld: At first glance, a reader might assume that increasing heteroplasmy would lead to more mtDNA mutations being transmitted. Can you simplify that concept?
Larsson: It may seem intuitive that higher levels of mutant mtDNA would facilitate mutation transmission, but our study shows that purifying selection is more efficient if mutation levels increase. A tighter bottleneck increases the heteroplasmy variance between individuals, but it also allows selection to act more efficiently. In other words, harmful variants can be identified and purged more effectively when individual mutations are present at higher levels.
MitoWorld: Can you expand on what triggers autophagy? It’s interesting that the one protein Bcl2l13 attaches mitochondria with a high HF ratio to the autophagosome.
Larsson: Autophagy is triggered by several cellular stress signals, nutrient limitation, energy imbalance, or structural damage to the organelles. In the germline, we think the process is tuned specifically to identify dysfunctional mitochondria. Bcl2l13 appears to act as a recognition factor, marking mitochondria with a high proportion of mutant genomes for degradation. This selective role is still only partly understood, but it suggests a remarkable level of specificity during mtDNA transmission.
MitoWorld: The conservation of aspects of these mechanisms across most metazoa is interesting. Most eukaryotes feature maternal inheritance of mitochondria. These mechanisms must have evolved very early in evolution. Any speculation?
Larsson: Yes, these systems likely arose very early. Once organisms started relying on oxidative phosphorylation, mutations in the mitochondrial genome became a genuine threat to fitness. Mechanisms such as bottlenecks and selective degradation would have been strongly favored by evolution. Their conservation suggests they were effective solutions and have remained largely unchanged across hundreds of millions of years.
MitoWorld: Your extensive work on mitochondria has covered many topics, including cancer, inflammation, obesity, and much more. Is the central role of mitochondria in all these areas a function of energy production or are there other activities involved?
Larsson: Energy production is certainly fundamental, but mitochondria do far more. They influence signaling pathways, metabolite synthesis, innate immunity, and cell death. Their dysfunction sends ripple effects through many biological systems, so it is not surprising that mitochondrial defects appear across diverse diseases. Understanding mtDNA inheritance is one aspect of a much broader picture of mitochondrial biology.
MitoWorld: Can you imagine how your findings might be translated into clinical treatments? Will your lab be following up on that possibility?
Larsson: We are cautious about translating findings prematurely, but the work does suggest conceptual avenues. If we can identify the key factors that guide purifying selection, it may eventually be possible to enhance this process in patients carrying pathogenic mtDNA variants. Our immediate focus remains on basic mechanisms, but we collaborate closely with clinical groups, and we certainly see therapeutic potential in the long term.
MitoWorld: In you brief bio on the MitoWorld website, you stated that you became interested in mitochondrial DNA in diseases during your PhD training. Since then, you have contributed significantly to the understanding of mitochondria. Could you comment on your thoughts on these organelles today?
Larsson: My appreciation for mitochondria has only deepened over the years. They are extraordinarily dynamic organelles, genetically, metabolically, and evolutionarily. What continues to inspire me is how much remains unknown. Every time we think we understand a pathway, we find additional complexity. That curiosity is what keeps our field vibrant, and I believe mitochondria will continue to surprise us for many years to come.
Reference
Kremer LS, Golder Z, Barton-Owen T, Papadea P, Koolmeister C, Chinnery PF, Larsson NG (2025) The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy. Science Advances 11(46): eaea4660.
The energy resistance principle (ERP) describes behavior and transformation of energy in the carbon-based circuitry of biology. We show how energy resistance (éR) is the fundamental property that enables transformation, converting into useful work the unformed energy potential of food-derived electrons fluxing toward oxygen. (Picard, Murugan)
In a recent Perspective published in Cell Metabolism, Drs. Martin Picard and Nirosha Murugan offer a new perspective about the nature of living systems that amounts to a powerful tool for life scientists to orient themselves amidst the seemingly infinite convolutions of biology. They call it the energy resistance principle (ERP), and, bearing a tantalizing resemblance to Einstein’s mass-energy equation, it states that EP = éR⋅f2, where EP is energy potential, éR is energy resistance, and f is electron flux.
The deep insight of the ERP derives from its recognition that living systems, from the scale of organisms to organelles, are analogous to electrical circuits. In the same way that the Power law (P = R⋅I2) captures how current flowing through resistive elements converts electrical energy into heat or mechanical work, the ERP contends that the energy behavior of living systems ultimately comes down to the flux of electrons from food to oxygen. In its path, the flow of electrons meets resistance through the myriad mechanisms of the body itself, with its cells and organs, continuously perfused by a vast and undulating network of blood vessels, driving countless enzymatic activities across layers upon layers of membranes to maintain homeostasis.
Indeed, from the perspective of the ERP, we can chart the movement of electrons across the body as a simple electrical flow diagram, where the organism and its metabolism behaves like an integrated electrical circuit. Derived from photosynthesis, the food we eat carries electrons into our bodies as we ingest it; and these electrons are ultimately attracted by the electronegative force of molecular oxygen, held in place by respiratory complex IV embedded within the folds of the inner mitochondrial membrane (IMM).
Importantly, the electrons stored in carbohydrates, fats, and proteins, have a long journey from the mouth to the mitochondrion. Our teeth and a host of enzymes along the gastrointestinal tract break down these macromolecules into individual carbohydrates, fatty acids, and amino acids enabling their selective transport across the walls of the intestines and conveying them into the circulatory system to be dispersed to the trillions of cells that depend on them. After arriving at the plasma membrane of a cell, however, a glucose molecule, for example, still must pass through one of a number of GLUT transporters and be shuttled through glycolysis where it is converted into pyruvate, before being imported into the mitochondrial matrix. In the matrix, pyruvate’s electrons are moved along the citric acid cycle and carried by NADH to the electron transport chain, which pumps hydrogen ions across the IMM, forming a proton motive force, which, in turn, is consumed by the ATP synthase to generate the molecular energy carrier, ATP. Step by step, as electrons get closer and closer to molecular oxygen in mitochondria, they encounter energy resistance (éR) that enables energy transformation (e.g., chemical to electrical). It is important to note that if there were no resistance there would be no transformation. Ultimately, this incremental resistance to the flux of electrons is harnessed to perform work of all different kinds, which sustains life from moment to moment.
Picard and Murugan argue that what we call health and disease is best understood through the lens of the ERP, where either too much or too little energy resistance is incompatible with life. Molecular theories of biology, health, and disease are appropriate to address some important questions, like designing an antibiotic against the molecular feature of a bacterial ribosome. But molecular theories have yet to yield the hoped-for insights into complex health/disease dynamics in humans.
Whether the ERP turns out to be true depends on whether it can be falsified: i.e., can it be rigorously put to the test? Intriguingly, as the authors note, we are already aware of the results of a key experiment: What happens to a living system if the flux of electrons (i.e., f) is blocked by cyanide, the respiratory chain poison that interferes with the binding of oxygen to complex IV? According to the formulation éR = EP/f2, the electron flux would approach zero, sending the energy resistance to infinity, which is another way of saying that the organism would die. Conversely, if the system contained a superabundance of mitochondria, possessing, theoretically, an unlimited capacity for electron flux, the energy resistance would go to zero, precluding the ability to perform useful work. These situations emphasize an important aspect of the ERP—namely, that in the flux of electrons from food to oxygen, there is a sort of goldilocks zone of energy resistance according to which the organism will approach optimal health; and, critically, the symptoms of disease are tantamount to deviations from this favorable zone.
In the final analysis, the ERP represents a durable framework according to which biologists can bring everything back to the bioenergetic girders of complex physiological processes. What’s more, the authors invite life scientists to put their formulation to the test. While they recognize that it may require further elaboration, the ERP promises, at the very least, to serve as a useful scaffold for understanding how living systems operate, because, at its core, it emphasizes that there is no life, and therefore, no health, without the continuous flux and transformation of energy.
MitoWorld: It is far from routine for biologists to endeavor to formulate general principles of life. What compelled you to look for basic biological trends that could be boiled down into an equation?
Picard and Murugan: We were motivated to address a central gap in biology. Biomolecular descriptions tell us what the components are, but they do not explain how living systems coordinate energy flow in time and space or why physiology and behaviors obey energy constraints that molecular biology alone cannot account for. Empirical work across mitochondrial biology and whole-body energetics shows principled relations among energy potential, electron flux, metabolic demands, and stress responses, pointing to an underlying energetic basis shaping how organisms function.
So our aim was to address this missing link by building a quantitative framework that connects energy flow to the behavior of living systems, grounded in the same physical constraints that govern how energy moves and transforms in other, simpler domains of physics. The Energy Resistance Principle (ERP) emerged as a physics-inspired heuristic to formalize these empirical patterns—mostly from the physics of electricity and the Power Law. Expressing the relation among energy potential, flux, and resistance created by biological structures provides a simple way to understand and describe how organisms regulate energy transformation and how this regulation shifts across health, aging, and disease. We don’t propose the ERP as a universal law, but as a biophysical scaffold that bridges biology and energetic principles to interpret data and generate questions about how organisms transform energy across scales.
MitoWorld: The presentation of this principle focuses on the role of oxygen in the mitochondrial electron transport chain as the ultimate sink for the flux of electrons. How can this principle apply to rare eukaryotes that have lost their mitochondria or to archaeal or bacterial life forms that do not make use of oxygen?
Picard and Murugan: When systems are alive, electrons must move from donor to acceptor, like in an electrical circuit. Energy must flow. This flux is the defining signature of life. The ERP is not restricted to oxygen-based respiration but to the more general process of energy transformation through boundary conditions that create resistance. Oxygen happens to be the terminal electron acceptor in most eukaryotes, but the same logic applies to any system in which energy flows through gradients and encounters resistive constraints. In anaerobic bacteria and archaea, other molecules such as sulfur, nitrate, or carbon dioxide serve as electron sinks, and the resulting redox cascades similarly generate transformation through energy resistance.
In rare eukaryotes that have lost mitochondria, alternative metabolic circuits still regulate electron flow through non-oxygen redox systems. Cytosolic and organellar enzymes enable electron transfer to other acceptors, preserving the gradients required for energy transformation and information processing. These reactions maintain a measurable resistance to electron flow, allowing energy to be converted into chemical work that sustains metabolism and repair. What matters is not necessarily the particular molecules involved, but the physical principle that a finite resistance to energy flow is required for transformation. This boundary or constraint, which is where that energy meets resistance is transformed, marks the distinction between life and non-life.
The ERP therefore emphasizes the physics of energy transformation rather than the species-specific biochemistry of that enables and subserves energy transformation.
MitoWorld: If you had unlimited resources and time, how would you test the ERP empirically?
Picard and Murugan: One key element of the ERP that appears critical is the oscillation, or regular shift between low and high energy resistance states. For example, states of high activity, followed by states of relaxation. That’s how neurons work—firing, then relaxing (refractory period). That’s also how the heart works—systole, then diastole. Cell division also goes through similar phases of the cycle.
In humans, at the scale of the whole body, we see this phenomenon manifest in the sleep-wake cycle. We’d love to know if energy resistance at the whole-body level fluctuates between high éR during wakefulness, and low éR during sleep. We know that a number of things that contribute to energy potential decrease during sleep—muscles stop contracting for example, heart rate decreases, cortisol is at its lowest. This is predicted to decrease energy potential. And if EP drops, flux should also decrease—which is what happens. We’d love to run 24-hour studies where we can monitor whole-body physiology and blood biomarkers (metabolites, proteins) in parallel with sleep stages, to ask what happens with éR when we sleep and the body enters the state of repair and restoration. Good evidence shows significant energetic shifts also during states achieved with meditation and mindfulness—do these things have positive health effects because they reduce éR? With unlimited resources, we’d measure this in at least a hundred people, on multiple day-night cycles to see how stable these patterns are. We’d also use non-invasive methods like magnetic resonance, biophotons, and bioelectricity to tap into the systems’ integrated energetic state.
MitoWorld: The ERP resembles the Power law. What distinguishes it from a nonliving electrical system involving power (P), current (I2), and resistance (R)?
Picard and Murugan: Nonliving electrical systems are closed circuits built from fixed components. These systems do not sense or respond to the energy moving through them. They simply dissipate or convert energy according to their material properties. Because nothing inside the circuit adapts, its resistance, current, and power are fully determined by the hardware and remain static unless the circuit is deliberately altered from the outside.
Living systems, like our bodies, operate very differently. They are open systems that take in energy and matter and rely on energy transformation to sustain their existence and go against entropy. In animals, internal resistance is continuously reshaped by physiological processes. Cells, membranes, enzymes, and mitochondria actively adjust their resistance as nutrient supply, oxygen availability, hormonal signals, and metabolic demands shift. Blood vessels dilate or constrict, mitochondrial content changes with training or stress, and whole-body physiology reallocates energy across organs depending on need. Our subjective experiences and behaviors, too, we suspect, reflect éR. These adaptive networks allow energy flow to be redistributed and transformed in real time to maintain function, support recovery, and prevent damage. The ERP leverages the relationships within the Power law to this physiological setting by framing resistance as a variable that organisms generate and tune to sustain life.
MitoWorld: The modern world is beset by a range of metabolic diseases, from diabetes mellitus to cancer. How can the ERP shed light on the nature of these disorders and provide insights into how to mitigate them?
Picard and Murugan: Simply put, we can understand diseases as energy sinks. Diseases arise when the system’s components can’t perform their normal functions optimally. This diverts resources—energetic resources, towards the dysfunctional component in an attempt to mend, repair, or restore function. That’s the healing process—an energy-demanding, dynamic process. When analyzed molecularly, through transcriptomics, for example, almost all diseases feature an upregulation of various genes. The system is struggling and mobilizing pathways, enzymes, components to cope. But nothing is free in biology. Resolving a disease requires additional work being done. Genes expressed. More blood flow. Cytokines. And all sorts of things that we think contribute to raise the energy potential (EP) of the system. If the system can increase flux to match the demand, éR doesn’t creep up too much. But if flux is limited by evolutionary-driven physiological and biological constraints, then diseases should chronically elevate éR. We think that’s why diseases accelerate damage accumulation and biological aging.
Seen through the lens of the ERP, diseases localized or systemic elevations in éR. And healing is the set of processes that aim to restore éR back to normal.
MitoWorld: Conversely, more and more people are taking an active interest in optimizing their health. How can appreciating the ERP help people achieve their health goals?
Picard and Murugan: Appreciating the relationship between the flow of energy and resistance through the ERP allows us to think about health in a more integrated and actionable way. Instead of focusing on isolated organs or single biomarkers, the ERP reframes our perspective towards how energy moves through the body and how that flow is shaped by daily behaviors. Every experience that changes metabolic demand, circulation, mental states, or mitochondrial activity influences the resistance that energy encounters as it flows through our body. When resistance is persistently too high, in states of disease for example, we think that feels like fatigue—that would be why fatigue is the most universal, cross-diagnostic marker of any disease.
Beyond what’s described in the initial ERP paper, we suspect that health emerges from maintaining a dynamic éR balance. Not staying in a constant low resistance state but moving within a goldilocks zone or high and low resistance. Like the firing-resting neuron, the contracting-relaxing heart, and the waking-sleeping body. Seeing the body as an energetic process helps explain why simple behaviors matter. Why we need to sleep (period of low éR). And why eating all the time and never feeling hungry is damaging to our health—overeating increases éR, while fasting likely decreases éR.
When we start to see the body as an integrated network that uses energy flow as information, it also becomes easier to connect the biochemical and physiological layers. Molecules and pathways are snapshots of a deeper, dynamic energetic process. Social connection, meaningful interaction with the environment, the types of food we eat, and states of calm or stress all influence these biochemical signatures because they change how energy moves.
Finally, this energetic perspective codified as the ERP helps make sense of emerging therapeutic tools that work through non-chemical modalities. Light, magnetic fields, electrical stimulation, breath work, temperature, and other energetic interventions could work by shifting resistance to energy flow in quantifiable ways that are harder to make sense of molecularly. For example, near-infrared light therapy could act directly on the mitochondrial electron transport chain to facilitate electron flow—thus, decreasing the system’s éR. Because éR propagates through our biological circuitry (as redox balance and other intermediates) such a change in éR would be expected to influence metabolism at every step of the way from cellular energy metabolism to blood glucose, as a recent study suggested. All of which could happen without a single molecularly tractable alteration or change in gene expression.
Thinking in terms of energy and resistance provides a common language for linking diverse inputs ranging from the biochemistry of food, macronutrients, and light to physiology, health, and disease states.
MitoWorld: Life inevitably requires energy to survive and replicate. Can the ERP help us to understand the origin of life on Earth?
Picard and Murugan: Big question! It is unlikely that the ERP can directly explain the origin of life on Earth, we should be cautious about making that leap. But what it can offer is a way to articulate the energetic conditions that must be satisfied for any system to transition from non-living chemistry to organized, self-regulating processes.
All matter contains energy, but what differentiates living systems is their capacity to transform that energy in a controlled manner. All matter holds energy. Matter, in a way, is raw energy crystallized or brough into stillness, in material form. But living systems are defined by their ability to transform that energy into work, structure, and information. What the ERP says is that this transformation is only possible when energy encounters the right biophysical constraints. It must meet a boundary, a surface, or a substrate that shapes its flow and allows the stored potential to become something functional/useful.
Seen from this angle, the emergence of life becomes a question about where early Earth provided the right kinds of energetic gradients and the right kinds of constraints. Environments such as mineral interfaces, hydrothermal vents, and redox-rich surfaces could have supplied both the right energy potential and the resistive structures needed for primitive transformations. While the ERP does not claim to describe this origin, it highlights the importance of temporal and spatial dynamics that are often underemphasized in purely molecular explanations for life’s origin. The way energy moves, is constrained, and transformed across different materials may have created the conditions for simple chemical systems to create information (i.e., patterned energy), encode that information in relatively stable forms (Schrödinger’s “aperiodic crystal,” DNA), grow increasing complexity, and become what we now recognize as life.
MitoWorld: In the same way that Einstein’s mass-energy equation appears to be universal, do you expect that the ERP will be applicable to life that may have arisen and evolved on other worlds?
Picard and Murugan: The ERP is not presented as a universal law, and we do not assume it would apply to life that evolved under very different physical or chemical conditions. Whether life elsewhere would follow the same relationships is unknown because we do not know how the energetics of another environment would shape the constraints that give rise to resistance. Resistance is not a fixed quantity. It emerges from the particular substrates, structures, and boundary conditions available to a given form of life. If the chemistry, temperature, or energy sources of another world were fundamentally different, the pattern of constraints, and therefore the nature of resistance, could also be different.
What does seem fundamental is that for energy to be put to meaningful work, it must be transformed, and transformation requires resistance of some kind. Energy flowing without constraint cannot build structure or sustain function. Think of a photon beaming in outer space, never hitting anything, without any possibility of slowing down—no transformation possible. It is the interaction between energy potential and the resistance imposed by matter that creates the possibility for work, organization, and information. The ERP is one attempt to formalize this relationship for carbon-based, living systems on Earth.
What the ERP does provide is a framework that encourages us to look for measurable links between energy potential, flux, and the constraints imposed by biological structure. If we want to build a truly universal energetic principle for life, we will need to approach it in this way—not just molecularly, but energetically. By identifying patterns, defining their boundaries, and designing experiments that test them. It will take time, more data, and likely several iterations.
Perhaps one day we may arrive at a formulation that is broadly universal, but getting there requires first learning how to describe life energetically and recognizing the kinds of relationships that matter.
MitoWorld: Energy and information are both fundamental to life. Insofar as they are distinct parameters, which do you view as more fundamental to biology?
Picard and Murugan: In our view, energy and information are deeply interdependent in biology. Energy flow creates the conditions that allow living systems to sense, interpret, and respond to their environment. Information is the pattern that emerges from those energetic processes.
When cells adjust their resistance to energy flow, they are not only regulating metabolism but also encoding something about their internal state and the demands placed on them. This gets encoded temporarily as metabolite concentrations, which reflects information (an energy pattern) at a given point in time. If this pattern persists, and the metabolite concentration remains a certain way, that’s meaningful information the (epi)genome has evolved to respond to. So you get changes in gene expression. That’s yet another way to encode information, by changing the levels of mRNAs. Which then become proteins, an even stabler later of information encoding. If you keep going down that path, you get to organelles, cells, and whole organisms. That’s growth, development, and healing—the encoding of information, fundamentally energy patterns, in physical forms. In a way, growth and development are the accretion of matter, shaped by éR that patterns energy into self-enduring biological structures. Quite amazing.
At the level of whole physiology, dynamic adjustments in éR allow the organism to learn from energetic conditions and change its behavior accordingly. So we have molecules like GDF15, which encode an energy pattern—excess energy resistance, in the case of GDF15—released by specific cells into the bloodstream to alert the brain. In that sense, information arises from energy patterning, and the flow of energy is organized through information, making them two expressions of the same underlying energetic process that we are.
In a recent paper in iScience, an inter-institute research team led by Keisuke Kawata and his PhD student, Gage Ellis, examined the effects of repetitive head injuries in athletes with and without attention deficit hyperactivity disorder (ADHD). They found baseline levels of tricarboxylic acid (TCA) cycle metabolites were elevated in the ADHD group. After head injuries, both groups had lower levels, but the ADHD group had greater decreases. Thus, ADHD is associated with elevated baseline levels, but all athletes experience mitochondrial dysfunction after head injuries.
Athletes often suffer head injuries, and heading the ball is a common activity in soccer. The research team sought to determine the effects of subconcussive impacts of a normal soccer ball on mitochondrial function. They used a machine to launch a soccer ball at a specific speed to be headed by the player. Each player completed 10 headers. The researchers examined 25 players with and 25 players without ADHD by determined levels of TCA metabolites (e.g., oxaloacetate, citrate, isocitrate, pyruvate, alpha-ketoglutarate, and fumerate) in the blood before and after the head injuries.
Interestingly, they found that athletes with ADHD had elevated levels of citrate, isocitrate, malate, and oxaloacetate before the experiment. After the headers, both groups of athletes had lower levels, but the ADHD athletes had lower levels than the non-ADHD athletes. The ball impacts, although common in soccer players, had a significant effect on mitochondrial function.
These findings provide important insights into two key areas. While concussions have received a lot of attention in the last few years, players of other sports, such as soccer and basketball, are at risk for head injuries. Soccer is an extremely popular sport among young athletes these days. ADHD has become more common. Lower levels of citrate and oxaloacetate are assumed to indicate reduced energy production, and higher levels of the metabolites indicate increased energy demand. This study links mitochondrial dysfunction to both of these conditions and, in so doing, points to potential strategies to prevent or treat those injuries.
Discussion with Dr. Kawata and Mr. Ellis
MitoWorld: [Kawata] These findings are very relevant to the prevalence of ADHD and soccer among young people these days. Can you give us an indication of what direction your research might go in to advance these findings?
You’re absolutely right. Our findings have broad relevance beyond just soccer. Many athletes in contact sports experience repetitive head impacts, and brain energy metabolism is a key marker of healthy brain maturation and aging. Regarding ADHD, one important next step is to understand how psychostimulant medications might modulate the brain’s response to subconcussive impacts. We’re also very interested in exploring potential countermeasures for these head impacts, since we still don’t have an effective prophylactic agent that can truly enhance brain resilience against repetitive trauma.
MitoWorld: [Kawata] The injury model used in the experiment was much more mild than the injuries incurred in many contact sports. Do you have any plans to look at patients after more serious injuries?
I think the real novelty of our work lies in studying these more subtle impacts rather than the obvious, severe injuries. Cellular responses to major brain trauma have been explored for decades, but what’s fascinating is that even something as mild as 10 soccer headers can trigger dramatic changes in TCA cycle metabolites. That’s a completely new insight. So rather than moving toward more serious injuries, we plan to keep focusing on this subconcussive spectrum of brain trauma. It likely carries broader implications for athletes and everyday populations.
MitoWorld: [Ellis] Can you speculate on how ADHD might be linked to enhanced levels of mitochondrial activity as evidenced by the higher levels of those compounds?
The athletes with ADHD that participated this study were all ingesting prescribed ADHD medication. There are several different types of ADHD medication, the most common of which are stimulants. Psychostimulant ADHD medication functions by altering dopaminergic and adrenergic pathways, specifically at the postsynaptic cleft. By binding to dopamine and norepinephrine receptors, neurotransmitters released by the presynaptic cleft are then reabsorbed. It is possible that the extracellular level of neurotransmitters and increased binding of synaptic receptors could alter the ionic state of the cell, upregulating ATP demand and then in turn increasing metabolic demand prior to exposure to head impacts. Another potential link to increased energy metabolite levels at baseline would be ADHD stimulant medication’s role as an immunomodulator, in which it has been reported to increase brain-derived neurotrophic factor, as well as suppress inflammatory interleukins such as interleukin-1 beta and tumor necrosis factor-alpha. In addition to modulation of pro and anti-inflammatory proteins, stimulant medication has shown to modulate oxidative stress as well, with evidence of both increasing and suppressing reactive oxygen species (ROS). While it is unclear the direction of modulation for ROS, it is notable that ADHD medication does play a role in oxidative stress and therefore could be the source of the enhanced mitochondrial activity denoted in this study.
MitoWorld: [Ellis] Can you envision a therapy for ADHD or head injuries that might involve treating mitochondria?
There are several different possible therapies for ADHD and for head injuries that include modulating mitochondrial function. One potential intervention would be pretreating with omega-3 fatty acids such as eicosapentaenoic and docosahexaenoic acid, which reduce oxidative stress and reinforce cell membrane structural integrity. Another potential therapy for head injuries, as well as ADHD, that also affect the mitochondria would be graded aerobic exercise. Currently, graded incline treadmill walking is a common protocol to treat concussions by reducing symptoms and improving return to play in athletes. Exercise improves ADHD symptom expression in children and adolescents, as well as reduces pro-inflammatory interleukins in individuals who engage in regular exercise. In addition to treating head injuries and improving ADHD symptom outcomes, aerobic exercise helps to regulate glycolytic pathways and improve metabolism.
In spite of all of this, the type of exercise, the intensity, and therefore the dosage for improving ADHD symptoms has not been defined and therefore is unknown. In addition to this, the graded incline treadmill walking to improve concussion outcomes is also extremely heterogenous per the individual.
MitoWorld: [Ellis] Did you have enough ADHD athletes in your study to see increase risk with those with more severe ADHD?
For this study, although we had 25 individuals with ADHD participate in the study, we did not see an increased risk correlated with ADHD severity. However, given the ADHD participants were all using medication, it is possible that ADHD severity and symptom expression was dampened, therefore making it improbable that ADHD severity would be correlated with mitochondrial outcomes.
MitoWorld: [Kawata] How did you come to be interested in mitochondria in the first place?
My interest in mitochondria actually goes back to my master’s program, when I worked in a lab focused on mitochondrial biology. I studied brain mitochondrial biogenesis and mitophagy, which really sparked my fascination with how these processes sustain neural health. More recently, I was part of a study (Vike et al., 2022, iScience 25(1):103483) that found potential links between head impacts and mitochondrial energy deficiencies in American football players. However, the causal relationship was still unclear because human studies at the time weren’t well controlled. That’s what motivated us to use a metabolomics approach in a rigorously controlled trial, to better understand how mitochondria respond to subtle head impacts.
Reference
Ellis G, Nowak MK, Kronenberger WG, Recht GO, Ogbeide O, Klemsz LM, Quinn PD, Wilson L, Berryhill T, Barnes S, Newman SD, and Kawata K (2025) Alterations in mitochondrial energy metabolites following acute subconcussive head impacts among athletes with and without ADHD. iScience 28(6).
It’s time for a science of health, and a good look at the science behind the healing process. It looks likely that mitochondria play a central role in our ability to heal and be resilient. – Martin Picard, Columbia University
Martin Picard, PhD, runs the Mitochondrial Psychobiology Lab at the Columbia University Irving Medical Center. He and his students and colleagues, including Caroline Trumpff, a clinical psychologist and epidemiologist by training—now a mitochondrial psychobiologist—have deeply phenotyped healthy individuals and people with mitochondrial diseases. Picard, Trumpff, and the MiSBIE team devoted themselves to conducting psychological, stress and other biological investigations that are not strictly in the category of diseases, mutational consequences, or medical conditions. This has led to a rich body of investigations, studies and findings, including being part of a team that mapped mitochondrial distribution across all brain structures for the first time. Some of these investigations of energetics and stress do relate to underlying issues in medicine.
With NIH funding the Picard Lab assembled and led MiSBIE, a five year set of investigations and papers that will be reported out at the upcoming MiSBIE Symposium at Columbia University, and online, on December 12. The details are below, after MitoWorld’s interview with Dr. Picard.
MitoWorld: Martin, tell us about MiSBIE, how it came about, what it is.
Picard: MiSBIE is the Mitochondrial Stress, Brain Imaging, and Epigenetics Study. It was born in 2016, and it ran between 2018 to 2023. I put most of my startup funds into it—the most important study I thought my lab should focus on for the years to come. It was also the human translation of a 2015 preclinical study that showed that mitochondria regulate stress responses in mice. Now we’re 10 years later and we’ve learned a lot, which we’ll discuss at the Symposium on December 12th.
MitoWorld: Who should attend the 2025 MiSBIE Symposium?
Picard: Anyone interested in learning about mitochondria, stress, and health should find something of value at the symposium. Researchers in mitochondrial psychobiology and related fields may find details of the latest work in this area of interest. There will be relevant data and findings for clinicians who care for patients with primary mitochondrial diseases. And Mito patients may appreciate seeing the team unearthing new principles and findings that may eventually affect their care and empower them to achieve their full health potential. Entrepreneurs may also see opportunities in new mind-mitochondria connections discovered through MiSBIE. Finally, funders and philanthropists may find valuable lessons from the success of this deeply interdisciplinary study.
MitoWorld: Who is presenting and can you provide some URLs on what will be discussed, background papers?
Picard: Symposium presentations will be by scientists and students who have directly contributed parts of the MiSBIE study. You’ll hear directly from the team that conducted the study, and who are now performing analyses to understand the mind-mitochondria connection. The best background paper is the MiSBIE Mother Paper. Other MiSBIE data papers on the effects of mental stress on the metabokines FGF21 and GDF15, and on cell-free mtDNA, immune cell mitochondrial biology and symptoms, immune cell stimulation, and neuroimaging signatures have been published in final form or as preprints. All PDF are freely available on our website www.PicardLab.org/Publications
MitoWorld: What do you hope the outcome to be? What is the take away? And what do you hope to stimulate?
Picard: I hope people leave the MiSBIE Symposium inspired, with a new sense of the energetic processes underlying stress responses, brain processes, immune regulation, and the energetic cost of life. The key take away is that the energetic and molecular state of our mitochondria is linked to our experiences. More research is needed to bring energy into medicine, and to develop a more holistic model of what human health actually is. Most of biomedicine is about diseases—it’s time for a science of health, and a good look at the science behind the healing process. It looks likely that mitochondria play a central role in our ability to heal and to be resilient.
MitoWorld: Where can people register?
Picard: People can attend on Zoom or in person, and register at www.PicardLab.org/MiSBIE. We expect 400-500 people—there is room for everyone!
Details on the upcoming December 12 Symposium
The Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study was developed to understand the role of mitochondria and energy more generally in mind-body processes, as well as their potential relevance to people with mitochondrial diseases. At this Symposium, MiSBIE investigators and the international team of collaborators will share findings addressing some of the hypotheses we originally set out to test, plus some unexpected discoveries made along the way. The dataset and analyses conducted to date have linked mitochondria to immune, neuroimaging, endocrine, metabolic, psychosocial, and clinical outcomes relevant to the mind-mitochondria connection. We welcome you and your team to learn, discuss, question, and ideate to develop new collaborations.
The symposium will close with:
- Discussion around opportunities and future directions with the MiSBIE dataset.
- A poster sessionfor MiSBIE investigators and attendees wishing to present mitochondrial psychobiology-relevant research.
- A celebratory receptionwith mito-friendly food and drinks to commemorate MiSBIE’ success.
All of us need sleep, but the reasons for that need are poorly understood. Scientists have previously reported changes that occur in the brains of animals that have remained awake for long periods. However, it wasn’t clear if these changes are causes or results, and the physical basis of the need for sleep is still unknown.
In a recent paper published in Nature, researchers at Oxford University, led by Gero Miesenböck, argued that the only way to sort out this issue was to look at specialist neurons with known roles in inducing and maintaining sleep. To gain insights into what makes us sleepy, the Oxford scientists studied the fruit fly Drosophila and compared the genes turned on or off in sleep-promoting neurons of rested and tired flies. Interestingly, almost all the upregulated genes encoded proteins involved in mitochondrial respiration and ATP synthesis. Other effects of sleep loss included mitochondrial fragmentation, mitophagy, and more contacts between mitochondria and the endoplasmic reticulum. After sleep, all of these were reversed, and nearly everything returned to normal.
The Miesenböck team speculate that the reason why animals need sleep is their power-hungry nervous systems, whose energy demands can only be met by stripping electrons from foodstuffs and transferring them to oxygen. Oxygen, however, is a double-edged molecule because its chemical nature invites missteps in mitochondrial electron trades; electrons leak from the respiratory chain and form damaging reactive oxygen species. This, they suggest, is the root cause of sleep.
The authors also note that neurons regulating sleep and energy balance work through similar mechanisms. These mechanisms involve cycles of mitochondrial fission and fusion. Fusion increases weight gain and fat deposition and also sleep. Hindering fusion does the opposite.
They conclude that sleep, like aging, may be an inescapable consequence of aerobic metabolism. Their findings enhance the understanding of how sleep is controlled and why we need sleep. The deeper understanding of sleep might also eventually point to potential new strategies for helping patients with sleep challenges.
A Conversation with Dr. Miesenböck
MitoWorld: What do you see as the next steps in your research?
There are two obvious follow-up steps. The first is to ask whether mitochondrial respiration also regulates mammalian sleep, or whether this is a fly thing. I definitely think it is not, but it still needs to be proven formally. The second question relates to the function of sleep. We may have put our finger on the cause—electrons spilling from mitochondria—but how sleep prevents or repairs the resulting damage remains unexplained.
MitoWorld: Multiple theories try to explain the need for sleep. Your work adds real observations to the idea of sleep as an ancient metabolic need for energy-consuming brains. Is this likely to be enough to tip the scales in favor of mitochondria?
Maybe there are no scales to be tipped because sleep has many functions and most theories will turn out to be correct. In our view, sleep originally evolved because neurons consume a lot of oxygen to support their energy needs. Once mitochondria had forced rest periods on animals, other functions were likely added, such as the downscaling of synapses strengthened during waking or memory consolidation.
MitoWorld: You described how you deprived the flies of sleep in your methods section, but I can imagine that readers might be wondering how you keep flies from sleeping. Could you briefly summarize that process and also how you induced sleep in the flies?
We deprived the flies of sleep just like we would deprive you: by poking them every 10 seconds or so. Fortunately, we have a machine that does that.
MitoWorld: You note a connection between sleep and eating and the need to maintain a balance for each of these key physiological processes. Can you elaborate on that?
Both sleeping and eating are, to use an old-fashioned term, drives: basic needs regulated by feedback. The less you sleep, the more tired you are; the less you eat, the more hungry you are. We now know that the neuronal controllers of sleep and hunger are similar in that they both depend on cycles of mitochondrial fission and fusion.
MitoWorld: This study features some very nice technical work (e.g., selection of an organism with cells known to be involved in sleep, a key fluorescent marker for selection, single-cell transcriptomes). Can you comment on those?
Thank you. My favorite of the many clever experiments Raffaele Sarnataro did draws on the concept of optogenetics, which we originated a quarter of a century ago. Raffaele put a light-driven proton pump into the mitochondria of sleep-promoting neurons and powered ATP synthesis with photons rather than electrons. This made electrons redundant and put flies to sleep.
MitoWorld: Could you speculate on whether your findings can be extrapolated to humans?
There are some hints. For example, an overwhelming sense of tiredness is a common symptom of human mitochondrial disease, despite normal ATP levels and no muscle fatigue.
MitoWorld: How did you come to be interested in mitochondria in the first place?
A previous study from my lab (Kempf et al., Nature 2019) provided the first clue that mitochondria are involved in the regulation of sleep. We discovered that sleep loss increases reactive oxygen species (ROS) in sleep-control neurons and that curbing electron leakage in their mitochondria (which fuels ROS production) reduces the pressure to sleep. In the present study, we played dumb and pretended we knew nothing about how sleep-control neurons sense the need for sleep. And voilà, when we looked at gene expression changes with a completely open mind, mitochondria popped up again.
Reference
Sarnataro R, Velasco CD, Monaco N, et al. (2025) Mitochondrial origins of the pressure to sleep. Nature 645: 722–728. https://doi.org/10.1038/s41586-025-09261-y