MitoWorld

The health of skeletal muscle is critical to overall wellbeing. While the loss of muscle mass and force is associated with aging, shortened life span and multiple chronic diseases, physical activity, which is thought to improve overall muscle health, is widely viewed as important for health and quality of life. Despite the significance of skeletal muscle to health, until now, no coherent model has sought to conceptually integrate the various aspects of muscle homeostasis.

Recently, a group of international scientists, led by Marco Sandri (University of Padova) and Anna Vainshtein (Craft Science), proposed a unifying framework that spans metabolism and bioenergetics, proteostasis, genomics, excitability, structure, regeneration and crosstalk. They hope that this framework will facilitate the development of new diagnostics and therapeutics. The consensus was published in Nature Metabolism.

The authors note that this framework and its hallmarks should enable researchers and clinicians to develop effective strategies for muscle-related disorders. They believe it is particularly timely with the popularity of GLP-1 receptor agonists and other treatments that promote weight loss as their effects on overall muscle mass and function are of great interest.

Not surprisingly, mitochondria figure into several of the hallmarks. Metabolism and bioenergetics obviously involve mitochondria, but these organelles also have significant functions related to other hallmarks. Mitochondria play a major role in proteostasis and are specifically important in programmed cell death and autophagy. Autophagy is also vital for excitability at the neuromuscular junction while ATP production is important for muscle structure. All of the hallmarks are further integrated in multiple ways.

The framework describes mechanisms and measures for each of the seven hallmarks and demonstrates how they can be integrated to facilitate the development of diagnostics and therapeutics. It promises to be as valuable to the health of muscle tissue as similar frameworks have been for cancer and aging.

A Statement of Significance by Dr. Sandri.

Skeletal muscle biology has traditionally been largely siloed, with advances in various aspects occurring in parallel but largely separately. The field has lacked a holistic view in which a shared conceptual framework to explain how these processes act together to keep muscle healthy and how their failure produces muscle loss observed with aging or disease. That has made it challenging to identify efficient diagnostics and therapeutic interventions.

The Hallmarks of Skeletal Muscle Health proposes that structure. It describes seven interdependent properties: metabolism and bioenergetics, proteostasis, genomics, excitability, structure, regeneration and crosstalk, that together govern muscle integrity, adaptability and resilience.

The significance is not in naming these processes, most of which are well recognized, but in framing them as an integrated system in which perturbation in one hallmark propagates across the others. Each hallmark is defined mechanistically, and we propose ways to measure and modify it which takes the framework from theoretical toward real-world application. Our hope is that it resonates with the muscle research community and beyond, encouraging those in and outside the field to evaluate muscle health in a more holistic and comprehensive way. We also hope this can help illuminate knowledge gaps for future research and provide a roadmap for the development of better knowledge, diagnostics and treatments in skeletal muscle.

A Conversation with Dr. Sandri.

MitoWorld: It is early after publication, but can you say what has been the reaction of the scientific community to the framework so far?

Dr. Sandri: It is indeed still early, but I am cautiously optimistic. By looking at the altimetric score, the paper ranks 1^st In Nat Met and among the 99^th percentile of 202,818 tracked articles of similar age in all the journals. Therefore, the attention of scientists has been attracted by this publication. Most of the reactions I have seen so far have been overwhelmingly positive and very receptive. There is a genuine sense that the muscle field is due for this kind of attention, and colleagues seem pleased to see its biology organized into a coherent framework. I am happy to see people engaging with the framework actively and testing it against their own areas. That is most encouraging, because the value of the framework is in being used and tested.

MitoWorld: Can you speculate on what might be some of the early benefits of the use of the framework?

Dr. Sandri: I think the most immediate benefit is a common language and a shared map. At the experimental level, it encourages investigators to look beyond a single pathway or endpoint and consider whether an intervention changes several dimensions of muscle health.

The emphasis on measurability and modifiability was deliberately practical. Muscle mass is important, but an increase in mass does not necessarily mean proportional improvement in strength, metabolic competence or function. We have seen this experimentally and clinically. The framework encourages the use of mechanism-aligned biomarkers and multi-hallmark read-outs that may reveal dysfunction before substantial muscle loss has occurred.

We also hope this will help with clinical trial design. If we understand which hallmark a therapy is expected to modify, then biomarkers and endpoints can be selected to test that mechanism rather than relying only on relatively downstream measures. And for people entering the field, I think having an organizing structure through which to understand a very large body of literature is also valuable.

MitoWorld: Mitochondria have roles in so many key cell functions in addition to energy production. Can you comment on their importance?

Dr. Sandri: Mitochondria are central to muscle health and vitality. It is not simply a site of ATP production, though of course that role is essential in a tissue that must generate force over decades. Mitochondria are a hub that integrates energy production, calcium homeostasis and redox signaling, with gene regulation, excitability, proteostasis and regenerative competence.

Mitochondrial quality is maintained by a constant balance of fusion, fission and the selective removal of damaged organelles by mitophagy, and when that balance fails, dysfunctional mitochondria accumulate and contribute not only to muscle degeneration, weakness and fatigue but can reverberate locally and systemically by promoting the secretion of myokines. So, the organelle sits at the intersection of several hallmarks at once.

MitoWorld: Several of the hallmarks are also related to aging and cancer. Is there overlap between those earlier hallmarks and your muscle one?

Dr. Sandri: Yes, if you think about it, it makes complete sense for there to be overlap, after all the hallmarks that define aging also influence muscle health, such as proteostatic decline, mitochondrial dysfunction, genomic and epigenomic change, and altered intercellular communication, appear in the hallmarks of aging and in a tissue-specific form, in ours. But muscle has some peculiarities. It is a post-mitotic, protein-dense, force-generating tissue, and processes, such as excitability and the neuromuscular junction, sarcomeric structure, and satellite-cell-driven regeneration, are specific to it. So, I would describe the relationship as a shared foundation expressed through muscle-specific mechanisms.

MitoWorld: Can you describe some of your own research and how it relates to the hallmarks?

Dr. Sandri: Much of my work has been at the interface between proteostasis and mitochondrial biology and how mitochondria signal to the nucleus to promote adaptative responses. For many years, our laboratory has studied the signalling pathways that control muscle mass. Much of our work has focused on the systems that control proteins and organelles turnover, particularly the ubiquitin–proteasome and autophagy-lysosome. We were the first to show that these degradative systems are controlled by transcription factors and identified FOXOs as the master regulators. And despite our original hypotheses, we discovered that these pathways cannot be labeled as simply catabolic and therefore detrimental. FOXO activation can promote protein degradation and muscle atrophy, but basal autophagy is essential for muscle homeostasis. When autophagy is impaired in muscle, damaged proteins and organelles accumulate and the phenotype extends well beyond muscle mass, with mitochondrial abnormalities, sarcomere disruption, denervation and impaired regeneration.

The role of bioenergetics and mitochondrial quality became a natural extension of these questions. We have studied how the balance between fusion and fission regulates mitochondrial function and muscle mass, including the roles of fusion and fission proteins, such as OPA1 and DRP1, with balance playing a key role. Mitochondria must continuously remodel, and disrupting either side of this process has consequences for muscle metabolism and health that differs in terms of gene regulation, signaling pathways, calcium homeostasis, oxidative stress and muscle phenotype when the network is hyper-fragmented or hyper-fused. Our work has also shown that mitochondrial stress in skeletal muscle can travel beyond the fibre, generating signals with systemic metabolic effects.

For me, this illustrates the logic behind the Hallmarks framework. We often begin experimentally with one gene or one pathway because that is how we can establish causality. But a phenotype is typically more complex impacting multiple Hallamrks. A defect in autophagy impacts mitochondria, myofiber structure, contractile capcity and the neuromuscular junction. Moreover, mitochondrial dysfunction alters chromatin, promotes gene expression, disrupts proteostasis, metabolism and signalling, influencing muscle structure, regeneration and function. The framework is an attempt to connect these mechanistic observations into a more comprehensive view of muscle health.

Reference

Vainshtein A, Blaauw B, De Bock K, Munoz-Canoves P, Olson EN, Ottenheijm CA, Richter EA, Ruas JL, Schaffer L, Spiegelman B, Sandri M (2026) The hallmarks of skeletal muscle health. Nature Metabolism.

https://doi.org/10.1038/s42255-026-01595-9.

Cells face a continual metabolic decision: should fatty acids be stored for later, or mobilized and burned for energy? Mitochondria sit at the heart of both processes. Although they are best known for oxidizing nutrients to produce energy, distinct populations of mitochondria can also support the accumulation of cellular fat. Brown adipose tissue (BAT), which can rapidly shift between storing and consuming lipids in response to physiological demand, provides a particularly useful system for understanding how mitochondria help control this balance. A new study published in The EMBO Journal identifies mitochondrial calcium as an important signal at this metabolic decision point¹.

The current study builds upon previous work from the Shirihai laboratory at the University of California, Los Angeles, demonstrating that unique subpopulations of mitochondria coexist within brown adipocytes². One population, called peridroplet mitochondria (PDM), physically attaches to lipid droplets and preferentially oxidizes pyruvate, helping support lipid-droplet expansion. A second population, cytosolic mitochondria (CM), is spatially separated from lipid droplets and has a greater capacity to oxidize fatty acids. Thus, within the same cell, mitochondria can participate in opposing sides of lipid metabolism: supporting the build-up of stored fat or facilitating its utilization.

A pivotal question addressed by the new study is how cells transition between these states. To tackle this problem, the authors developed cell-free assays in which mitochondria and lipid droplets could be separated and then brought back together under controlled conditions. Remarkably, isolated PDM retained a greater intrinsic capacity than CM to bind lipid droplets. Their association was also influenced by the fuel available to mitochondria: pyruvate plus malate favored PDM attachment, whereas palmitoyl-carnitine, a fatty acid-derived substrate, favored detachment. The authors found evidence that these different metabolic signals converge on a common regulatory axis involving calcium within the mitochondrial matrix.

At the center of this mechanism is a transient rise in mitochondrial matrix calcium. During adrenergic stimulation, calcium enters mitochondria, and the authors found that elevated matrix calcium promotes a striking CypD-dependent architectural transition of PDM from their characteristic elongated, lipid-droplet-associated morphology toward a rounded, swollen form that favors detachment. Importantly, this represents a reversible mitochondrial shape transition rather than the irreversible mitochondrial damage associated with sustained calcium overload. Removing PDM from the lipid-droplet surface also increased the ability of recombinant lipases to liberate fatty acids, while blocking triglyceride breakdown did not prevent PDM detachment. Together, these findings place mitochondrial detachment upstream of lipid mobilization and support the idea that PDM can act as both a metabolic and a physical barrier to lipid utilization.

The duration of the calcium signal is tightly regulated. Following adrenergic stimulation, PDM and CM take up calcium at similar initial rates, but PDM clear it more slowly, exposing them to a larger and more prolonged calcium signal. The mitochondrial sodium/calcium exchanger NCLX counteracts this process by extruding calcium from the matrix and favoring mitochondrial association with lipid droplets. The authors further identified phosphodiesterase 2A (PDE2A), which is enriched in PDM, as an important regulator of NCLX activity. Inhibiting PDE2A accelerated NCLX-dependent calcium extrusion, preserved PDM association with lipid droplets, reduced fatty-acid mobilization, and increased glucose utilization.

The pathway was also manipulable in vivo. In obese ob/ob mice, three weeks of PDE2A inhibition produced a greater than fourfold increase in PDM abundance in BAT and increased glucose uptake by more than 50%, together with metabolic and morphological features consistent with BAT remodeling. Importantly, the study does not establish whether increasing PDM is itself responsible for this remodeling or whether PDM accumulation occurs as part of a broader change in the tissue. Nevertheless, the findings demonstrate that mitochondrial–lipid droplet interactions can be pharmacologically altered in a metabolically challenged animal.

Altogether, the study positions mitochondrial calcium not simply as a regulator of mitochondrial activity, but as a signal capable of changing mitochondrial positioning and, in turn, influencing how cells handle fat. Brown adipose tissue offers a particularly vivid system in which to study this principle because lipid storage and utilization can be rapidly switched in response to physiological demand. Whether analogous mechanisms operate in other cell types remains an intriguing question, with potential implications for understanding altered lipid metabolism in both physiological and disease states.

A Statement of Significance from Dr. Shirihai:

Brown adipose tissue provides a unique system for understanding how mitochondria can regulate both lipid storage and lipid utilization within the same cell. Our study identifies mitochondrial matrix calcium as a key decision point in this process: a transient rise in calcium within peridroplet mitochondria promotes their detachment from lipid droplets and shifts the cell toward fatty acid mobilization. This translates into a shift in fuel preference, toward lipid utilization. Beyond fuel, detachment of mitochondria may facilitate the release of lipids for signaling. A byproduct of this study was the investigation into the role of metabolites in inducing attachment and detachment through calcium. Investigation into this question revealed that mitochondrial matrix calcium is altered by specific mitochondrial fuels. Remarkably, acyl-carnitines elevate free matrix calcium, while pyruvate reduces it. This can explain various observations, including the previously reported induction of lipolysis by pyruvate carrier inhibitors.

But my favorite part of the study is the cell-free system that allowed us for the first time, to ask if PDM know they are PDM, and indeed they remember! If you separate them from a beloved lipid droplet, they come back and attach, and if you show them a lipid droplet from a white adipocyte they remain naïve.

Next is a manuscript about a PDM-detacher small molecule that induces lipolysis, shrinks lipid droplets, and inhibits viral proliferation.

A conversation with the authors:

MitoWorld: Brown adipose tissue provides a striking system for studying how mitochondria participate in both lipid storage and lipid utilization. As this story unfolded in the lab, which aspects of this metabolic switch surprised you most?

Authors: That metabolites are the actual signaling molecules for detachment and attachment, and that mitochondrial fragmentation has a new role: detachment via architectural change. Fragmentation also facilitates lipid import to mitochondria, as shown by by Ngo et al. EMBO 2023³. Therefore, fragmentation is critical for BAT to activate thermogenesis.

MitoWorld: Given that peridroplet mitochondria undergo cycles of attachment to and detachment from lipid droplets, how do you suppose that PDM maintain a unique identity alongside cytosolic mitochondria?

Authors: PDM remain faithful to lipid droplets. If separated, PDM have a higher affinity for binding to lipid droplets. The mechanism is likely to be through tethering proteins such as PLIN5, DGAT2, MIGA2.

MitoWorld: To what extent do you think distinct mitochondrial subpopulations exist in other cell types and are tailored to different physiological responses?

Authors: We already know that neurons have distinct mitochondrial populations in the neurites vs the soma, and other papers have shown that mitochondria isolated from purified nuclei have distinct functional features. The important implication is to consider that our research and therapeutic targets may be a subpopulation of mitochondria in a given cell type and as such we should design our studies to zoom in on them, exactly as we do in a mixed group of cells.

MitoWorld: Your findings suggest that mitochondrial calcium can influence whether cells favor fatty-acid storage or utilization. How broadly do you think this principle might apply to pathological alterations in lipid metabolism, such as those occurring in diabetes or cancer?

Authors: I think the principle could be much broader than brown adipose tissue. The important concept is that mitochondrial subpopulations can sense the metabolic environment and make a local decision between lipid storage and lipid utilization. In PDM, metabolites change matrix calcium and calcium becomes part of the switch that controls attachment to lipid droplets and access to stored fat. We do not yet know whether the same mechanism operates in other tissues, but many diseases, including diabetes, fatty liver disease and cancer, involve abnormal lipid accumulation or altered lipid utilization. It will be very interesting to ask whether similar mitochondrial decision points exist in these settings and whether they can be manipulated therapeutically.

MitoWorld: In a rodent model of obesity, pharmacological modulation of this pathway produced substantial metabolic remodeling in brown adipose tissue. With the advent of GLP-1 receptor agonists for treating obesity in humans, do you think targeting mitochondrial control of lipid metabolism could eventually provide an alternative or complementary strategy?

Authors: I see it more as a complementary strategy. GLP-1 therapies are extremely effective at reducing energy intake and body weight, while what we are studying is a different level of metabolic control: what happens to fat once it is inside the cell. The exciting possibility is that we may be able to control whether lipids are stored or mobilized by targeting specific mitochondrial populations and their interaction with lipid droplets. This could be useful not only for obesity, but also for diseases in which ectopic fat accumulation or abnormal lipid utilization contributes to pathology, such as diabetes, fatty liver disease, and potentially some cancers. The direction of the intervention may also depend on the disease: we may want to promote lipid utilization in one setting and limit it in another

MitoWorld: Can you elaborate about future directions for this research?

Authors: One direction is to understand the molecular machinery that gives PDM their identity and allows them to attach and detach from lipid droplets. Another is to understand how metabolites communicate with this machinery through mitochondrial calcium. But I am particularly interested in whether we can pharmacologically control this decision. We are now studying small molecules that promote PDM detachment, increase lipolysis and reduce lipid-droplet size. The larger question is whether manipulating mitochondrial–lipid droplet interactions can be used in diseases where abnormal lipid storage or utilization is part of the pathology. I think this will also teach us whether the PDM concept is unique to adipocytes or represents a more general principle of mitochondrial specialization.

References:

TRiMAD 2026, Early registration ends September 14 for an unusually accessible two-day gathering of leading mitochondrial researchers.

There are not many opportunities to spend two days in one place with mitochondrial researchers from the NIH, Harvard Medical School, Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, The Wistar Institute, University of Pennsylvania and Boston Children’s Hospital — alongside three of the major mitochondrial research centers in Philadelphia.

TRiMAD 2026 is one of them.

The Translational Research in Mitochondria/Metabolism, Aging and Disease Conference — TRiMAD — returns to Philadelphia November 14–15 for two concentrated days of mitochondrial science, from fundamental mitochondrial biology to cancer, cardiovascular and neurological disease, aging, metabolism and primary mitochondrial disease.

And unlike many major scientific meetings, TRiMAD remains deliberately accessible: early registration is just $125 for trainees and $200 for faculty. The early-registration deadline is September 14.

Three Philadelphia Centers Bring the Meeting Together

TRiMAD is organized by three institutions that have built significant mitochondrial research programs within a few miles of one another:

Thomas Jefferson University’s MitoCare Center, directed by György Hajnóczky, MD, PhD, brings together advanced imaging, mitochondrial phenomics and disease models to understand mitochondrial function and dysfunction across cells, tissues and disease.

Children’s Hospital of Philadelphia’s Center for Mitochondrial and Epigenomic Medicine, directed by Douglas C. Wallace, PhD, spans mitochondrial genetics and basic research through advanced diagnostics, translational science and clinical mitochondrial medicine.

Temple University’s Aging + Cardiovascular Discovery Center, led by John Elrod, PhD, brings mitochondrial biology into the study of cardiovascular disease and aging.

Together, these centers make Philadelphia an unusual concentration of mitochondrial research — and provide TRiMAD with a scientific range that extends well beyond any single definition of “mitochondrial disease.”

A Remarkable Group in One Room

The 2026 program brings some of the best-known names in mitochondrial science together with investigators pushing the field into new areas of medicine.

Dario C. Altieri, MD — The Wistar Institute. Dr. Altieri brings cancer squarely into the mitochondrial conversation. President and CEO of Wistar and Director of its Ellen and Ronald Caplan Cancer Center, his research explores mitochondrial mechanisms that allow cancer cells to adapt, survive and progress.

Zoltan Arany, MD, PhD — University of Pennsylvania. Chair of Penn’s Department of Physiology. Dr. Arany studies the molecular mechanisms linking metabolism and mitochondrial function with cardiovascular physiology and disease.

Edward Chouchani, PhD — Harvard Medical School, Dana-Farber Cancer Institute and HHMI. Dr. Chouchani is helping define a newer generation of mitochondrial research connecting metabolism, redox biology and mitochondrial signaling to cancer and metabolic disease.

Agnel Sfeir, PhD — Memorial Sloan Kettering Cancer Center. The PaineWebber Chair in Cancer Genetics at MSK. Dr. Sfeir investigates genome stability and mitochondrial DNA biology, bringing another important connection between mitochondria and cancer to TRiMAD.

Richard J. Youle, PhD — National Institutes of Health. An NIH Distinguished Investigator, Youle has been central to the discovery and understanding of mitochondrial quality control, including PINK1/Parkin-mediated mitophagy and its relationship to Parkinson’s disease.

Thomas Schwarz — Boston Children’s Hospital and Harvard Medical School. Dr. Schwarz studies how neurons maintain mitochondrial health, with a particular focus on mitochondrial transport, positioning, and local quality control/mitophagy in axons.

Rebecca Ganetsky — Children’s Hospital of Philadelphia. Dr. Ganetsky is a physician-scientist focused on primary mitochondrial diseases, particularly mitochondrial Complex V/ATP synthase disorders and mtDNA deletion syndromes, with an emphasis on connecting molecular defects to clinical phenotypes. Her translational work also develops new biochemical diagnostics and functional biomarkers of mitochondrial activity to improve diagnosis, disease monitoring, and ultimately therapeutic development.

Dmitry Temiakov — Thomas Jefferson University. Dr. Temiakov studies the molecular machinery that controls mitochondrial gene expression, using structural biology and biochemistry to define the mechanistic principles of mitochondrial DNA replication and transcription initiation. His work also examines how these processes are altered in disease or involved in physiological processes, like maternal inheritance of mitochondrial DNA.

John Elrod of Temple — Temple University. Dr. Elrod studies mitochondrial calcium signaling, metabolism, fibrosis, and cell death, particularly in the context of cardiac injury, heart failure, aging, and neurodegeneration. His lab is especially known for defining mechanisms of mitochondrial calcium transport and how altered calcium handling reshapes energy metabolism and contributes to disease.

More Than Keynotes

TRiMAD is designed for scientific exchange rather than simply a sequence of major lectures. Nine invited speakers will be joined by 20 short talks selected from submitted abstracts, two poster sessions and an opportunity to tour Jefferson’s MitoCare Center.

That makes the meeting particularly attractive for trainees and younger investigators who want their work seen and discussed alongside established leaders in the field.

TRiMAD began in 2011 as a way of bringing together mitochondrial researchers across the Pennsylvania-New York-Ohio-Michigan region. In 2026, its reach — and the range of mitochondrial biology represented — is considerably broader.

For MitoWorld, that breadth is particularly important. Mitochondria are increasingly being investigated not only in primary mitochondrial disorders, but across cancer, cardiovascular disease, neurological disease, metabolism, aging and other major areas of medicine. TRiMAD puts many of those conversations under one roof.

Don’t Miss the Early Registration Deadline: September 14, 2026

TRiMAD 2026
November 14–15, 2026
Dorrance H. Hamilton Building
Thomas Jefferson University
Philadelphia, Pennsylvania

Early registration through September 14:
Trainees — $125
Faculty — $200

Registration remains open through October 31, and abstracts may be submitted through October 14. Abstract presenters must be registered for the meeting.

MitoWorld will be following TRiMAD closely. This is the first of three MitoBlog posts leading up to the conference, including conversations with some of the scientists and organizers who are helping expand where mitochondrial science goes next.

All living organisms live in an environment shaped by gravity and other forces, but how do these forces affect gene expression? A multi-institute research team, led by Shintaro Iwasaki of RIKEN/the University of Tokyo, explored how mitochondrial translation is influenced by gravitational and mechanical forces. The study was published in Nature Communications.

After space flights, astronauts return to Earth with weak muscles. The mechanical stresses of gravity on Earth stimulate mitochondrial function, but without gravity, muscles atrophy from disuse. Previous research had documented damage to mitochondria during spaceflight. Multiple experiments on many space flights have shown various kinds of damage to cells and tissues. However, our understanding of those challenges is limited.

The Iwasaki research team sought to leverage and expand our knowledge of the effects of spaceflight on living organisms. They obtained samples that had flown in space. Frozen mammalian cells were flown to the International Space Station. In space, the samples were thawed, subjected to various treatments, and refrozen to return to Earth. Back on Earth, the researchers then used genome-wide ribosome profiling to compare mitochondrial translation in the spaceflight samples under microgravity and 1 G in the International Space Station. Caenorhabditis elegans samples were obtained from previous space flights.

They found that the samples had lower metabolic activity than Earth-bound samples. More specifically, mitochondrial translation was disrupted. Other cellular functions were affected, including loss of cell adhesion and radiation damage to the ECM. They looked at a poorly understood cell signaling pathway that connects cell adhesion sensing, mitochondrial malonyl-CoA balance, and translation. ATP production might still be found in the human cells, but mitochondrial translation was clearly affected in C. elegans. Other affected cell components included intermediate filaments and the apoptotic cascade.

While the connection between spaceflight and muscles atrophy was well-known, this study advances our understanding of how cells use gravity and other mechanical forces to regulate mitochondrial translation. It also provides valuable information that will help future astronauts to preserve muscle strength during extended space flights.

Statement of Significance by Dr. Iwasaki:
Gravity is a constant part of life on Earth, but we still know surprisingly little about how cells sense it. Our study shows that microgravity reduces mitochondrial translation. We also identified a pathway linking mechanical forces outside the cell to protein synthesis inside mitochondria. This may help us understand not only the effects of spaceflight, but also muscle disuse, aging, and mitochondrial disease.

A Conversation with Dr. Iwasaki:

MitoWorld: Can you give us an idea of how you might be thinking to extend the findings of this study?
Dr. Iwasaki: We would first like to identify the exact molecular mechanisms that could be affected by malonylation and control mitochondrial translation in response to mechanical forces. We are also interested in whether the same mechanism works in other tissues, such as the heart, bone, and blood vessels. Another important question is whether exercise, mechanical stimulation, or drugs could help maintain mitochondrial function during long-term spaceflight or physical inactivity.

MitoWorld: You mention in your Limitations to the Study section that you cannot eliminate other possible mechanisms that might affect mitochondrial translation. Can you speculate on what those might be?
Dr. Iwasaki: Malonylation is probably only one part of the story. Microgravity can also affect ATP/GTP energy balance, membrane potential, calcium signaling, redox balance, and many other metabolites. Changes in mitochondrial shape, protein import, RNA processing, or ribosome assembly could contribute as well. These are still open questions, and we will need more detailed biochemical and genetic studies to test them.

MitoWorld: How were you able to arrange to be a part of the experiments on the International Space Station?
Dr. Iwasaki: We applied to an open call from JAXA with a proposal to study how microgravity affects protein synthesis. The proposal was selected, and we then worked closely with JAXA and our collaborators to adapt the experiment for the ISS. We acknowledge the support from Japan Space Forum and Japan Manned Space Systems Corporation. The actual experiment was carried out in the Japanese “Kibo” module in 2021. Astronaut Soichi Noguchi performed the cell-culture work, and the samples were later returned to Earth for analysis. It was a long-term team effort involving researchers, engineers, and astronauts. We truly appreciate their extensive support that makes this project possible.

MitoWorld: The implications of your work for astronauts are clear. Might there be other clinical applications? For example, could the findings from the mouse experiments be useful to patients with limited mobility?
Dr. Iwasaki: Possibly, although we still need direct evidence from human studies. In mice, reducing mechanical load lowered mitochondrial translation in muscle. This suggests that a similar mechanism may operate during bed rest, limb immobilization, or age-related muscle loss. We are actively working to survey small-molecule compounds that may increase mitochondrial translation, as a potential means to treat sarcopenia.

MitoWorld: Mitochondria were found in many of the effects of spaceflight. Can you expand on why this might be?
Dr. Iwasaki: Because mitochondrial translation was already reduced within 24 hours of microgravity exposure, we suspect that this early response may contribute to other mitochondrial defects observed during spaceflight. To test this idea, we need more detailed and comprehensive time-course studies under microgravity conditions.

Reference
Wakigawa T, Kimura Y, Mito M, Tsubaki T, Lee M, Nakamura K, Khan AH, Saito H, Yamamori T, Yamazaki T, Higashibata A, … Iwasaki S (2026) Gravitational and mechanical forces shape mitochondrial translation. Nature Communications 17(1): 5552.
https://www.nature.com/articles/s41467-026-74493-z

Extended spaceflight presents many challenges to the human body, including the immune system. Effects have been particularly well-documented in the immune system. Recently, a team, led by Daniel Winer, Alexander Chouker, Christopher Mason and Brian Crucian, described those challenges and strategies for maintaining immune health in future astronauts. The review was published in Nature Reviews Immunology.

Humans evolved in an Earth-bound environment that featured gravity and a degree of protection from radiation. However, extended spaceflight presents many challenges to the human body. One of the most critical systems that might be negatively affected is the immune system. The many existing studies on space and the immune system, which have been elaborated by recent multiomic analyses, established the foundations of a new research field called astroimmunology.

For humans, space is a hostile environment with many threats, such as microgravity and cosmic radiation. In addition, microbes of the human microbiome display increased virulence, antibiotic resistance, biofilm formation and more. Space travel increases psychological stress and disturbances to circadian rhythms that affect the immune systems. For example, even minor respiratory infections seemed to be more common among early space station residents. If we are able to establish ourselves on the moon or Mars, new challenges from those environments will appear. All of these can impact our cellular health.

Unfortunately, it is hard to study these on the ground. There really is no substitute for experiments in space. It will be important to continue to explore the effects of space on human health as the number of flights increases. This outstanding review covers the many challenges and possible strategies to mitigate those effects. As spaceflights grow longer and longer, these studies will become even more important

A Statement of Significance by Dr. Winer.

The immune system is one of the body’s systems most impacted by spaceflight, typically showing a combination of basal low-grade inflammation from innate cells, coupled to reduced robustness, including by some adaptive immune cells, such as T cells. Since the immune system influences many physiological processes across the body, and its dysfunction contributes to most chronic diseases of aging, it is important to understand how changes to the immune system during spaceflight will ultimately contribute to astronaut health. Our work provides a comprehensive contemporary guide to understand how and why the immune system changes from stressors linked to spaceflight. It also covers pertinent topics like host-microbiome interactions, aging, clinical risks, countermeasures to boost immune function in space, immune monitoring, and how risks associated with living on the Moon or Mars could impact immunity.

A Conversation with Dr. Winer.

MitoWorld: Can you tell us the particular directions that your own research might take to further the findings described in this outstanding review?

Dr. Winer: We are currently working on a number of projects to better understand how changes in gravity, including simulated microgravity, impact immune cell function. We are also particularly interested in understanding how simulated microgravity can be used to recapitulate aspects of biological aging in the immune system. Working with the David Furman lab and Cosmica Biosciences, we have shown that 24 hours of simulated microgravity can induce aging trajectories in cells that overlap with natural processes as far as 9 years out. Thus, microgravity offers a chance to develop interesting new forms of prognostic markers in aging research. This test is the BeyondAge biological aging recently released by Cosmica Biosciences.

MitoWorld: The immune system is obviously critical to human health. Are you aware of other systems that are affected by spaceflight? For example, astronauts typically return from extended flights with atrophied muscles?

Dr. Winer: Spaceflight impacts most physiological systems, and in addition to the immune system, many astronauts will experience some declines or changes in musculoskeletal, endocrine, cardiovascular, and neurological systems (including sensorimotor), among others. We are particularly interested in the immune system since in theory, it plays a role in modulating so many diseases, such as cardiovascular diseases, musculoskeletal, metabolic, cancer, and neurodegenerative diseases. Thus, by studying the immune system, we can find potentially useful applications across many different diseases of aging, and complications of spaceflight.

MitoWorld: While you are focusing on space travel, could your findings have implications for clinical work here on Earth?

Dr. Winer: Yes. Since spaceflight stressors like microgravity and radiation alter fundamental cellular properties, such as DNA damage repair, mitochondrial function, cytoskeletal regulation, and inflammatory signaling, among others, all of which impact human diseases on Earth, we may learn more about fundamental processes driving such diseases. Such knowledge could be useful in designing new therapies, or biomarkers as alluded to previously.

MitoWorld: Can you briefly summarize the involvement of mitochondria in the effects on the immune system during spaceflight?

Dr. Winer: Mitochondria are key organelles that control immune cell activation, polarization, and programming. Through metabolic reprogramming, they can dictate the type of immune response that occurs in cells. For instance, pro-inflammatory macrophages and T cells often exhibit disturbed tricarboxylic acid cycles in the mitochondria, leading to increased usage of other pathways, such as glycolysis and the pentose phosphate pathway, that can support inflammation. During spaceflight stressors, we see a number of similarities. With simulated microgravity exposures, we see reduced mitochondrial oxidative phosphorylation across many immune cells, and this mitochondrial dysfunction can hamper immune cell functions. In addition, mitochondrial dysfunction in immune cells can lead to increased reactive oxygen species production which can also fuel inflammation. Finally, mitochondrial damage due to radiation from spaceflight can cause danger molecules to leak from the mitochondria and either lead to cell death or incite inflammation from cells. Thus, the mitochondria are a central hub impacted by spaceflight stressors on cells.

MitoWorld: Given the many challenges that you have cataloged with spaceflight, are you still hopeful about long-term space existence?

Dr. Winer: Yes! The study of astroimmunology and the impact of spaceflight on other physiological systems is still very young. For many years, due to technological limitations, most of these studies centered on basic phenotyping work, where we would see things, such as immune dysfunction, but not really understand fully in depth why the changes were occurring. However, now with more advanced techniques, such as many of the multiomic analyses as well as equipment that can perform terrestrial-like workflows in space, coupled to the increase of commercial spaceflights, we are seeing a major rapid expansion in knowledge understanding how spaceflight influences the body. With this new emerging knowledge, combined with other technologies, such as AI, I think that humanity will be in good position to develop robust countermeasures to facilitate safe space travel. Long-term space existence will no doubt continue to offer new challenges, but I am hopeful that such challenges can be overcome through interdisciplinary modern, and even futuristic approaches.

Reference

Winer DA, Du H, Kim J, Chang V, Burke M, Winer S, Costes SV, Frippiat JP, Sams C, Paul AM, Wu H, Ullrich O, Baatout S, Beheshti A, Mason CE, Choukér A, Crucian BE (2025) Astroimmunology: The effects of spaceflight and its associated stressors on the immune system. Nat Rev Immunol 26:189–212.

doi: 10.1038/s41577-025-01226-6.

The shapes and sizes of tissues and organs are critical to multicellular organisms, but the mechanisms controlling the different processes that generate them are only partially understood. A research team, led by Celeste Nelson at Princeton University, linked one of these shape-generating processes, apical constriction, to ATP production by mitochondria. The findings were published in Science Advances.

Apical constriction occurs when cells shrink on one surface to fold epithelial tissues. The force is provided by the contraction of actomyosin, and those actions require ATP hydrolysis. Thus, the pattern of ATP hydrolysis is critical. Dr. Nelson and her team sought to determine if the generation of that energy is also spatially patterned.

The team examined ventral furrow formation during gastrulation in Drosophila, neural tube closure during neurulation in chicken, branch formation during lung development in chicken, and lens placode invagination during eye development in mouse embryos. During development, these tissues use apical constriction to fold the epithelium in a well-characterized pattern. The researchers determined mitochondrial density by immunofluorescence staining for Tom20, an outer mitochondrial membrane protein. Using that and other tools (e.g., time-lapse imaging, spatial transcriptomics, oxygen consumption rate), they found that mitochondrial density, membrane potential, and ATP production are greater on the apical sides of epithelial cells during apical constriction. In fact, mitochondrial density can be used to predict which cells will undergo apical constriction before they initiate the fold.

During development, tissue shape depends on multiple factors, including gene expression, mechanical forces, and energy. These processes are remarkably conserved. The Nelson team demonstrated that the location of mitochondria predicts apical constriction and is upstream of other activities. Their findings implicate the spatial distribution of bioenergetics in development.

A Statement of Significance by Dr. Nelson

Many developing tissues generate their final shapes through a series of highly reproducible and stereotyped folds, akin to origami patterns. Over the past few decades, the field has uncovered many of the gene expression changes and biochemical signals that are necessary to generate the forces to fold these tissues. Our work now shows that ATP is generated at the site of folding before it begins by oxidative phosphorylation, and that mitochondria concentrate at these sites. So now we need to figure out whether the same genetic and biochemical signals are leading to both mitochondrial localization as well as force induction, or whether there are parallel signals.

A Conversation with Dr. Nelson

MitoWorld: Can you give us an idea of what direction your research might take to further your findings here?

Dr. Nelson: There is an increasing recognition in the field that energy metabolism and mechanical forces are interacting with each other on some scale within cells and tissues, and we’re seeing more and more research groups exploring these interactions, which is very exciting! Our group is primarily focused on branching epithelia, so we’re currently exploring the different ways in which epithelial branching morphogenesis is fueled across systems, whether it’s primarily by mitochondrial oxidative phosphorylation, or by glycolysis, or both.

MitoWorld: You focused on apical constriction in this work. Do you think the findings here can be extrapolated to other mechanisms involved in tissue morphology?

Dr. Nelson: Our data suggest that there’s an interesting coupling between energy metabolism and tissue folding. Since we published our findings, several other scientists have mentioned that they’ve also observed mitochondria at the apical side of their apically constricting tissues! So we think this observation might represent a conserved energetic-mechanical motif. But as your question suggests, tissues can fold in ways that don’t involve apical constriction. It makes sense to assume that other folding mechanisms require energy metabolism, but I wouldn’t be so bold as to predict that spatially patterned mitochondria are universal across types of folding events.

MitoWorld: Can you speculate on how mitochondria are controlled by the other elements of the signaling apparatus that determines tissue morphology? Your last sentence in the Discussion suggests the complexity of this question.

Dr. Nelson: The most stunning observation that we made, in my opinion, was that mitochondria appear at sites where energy is needed before the tissue folds. How do they know to get there? What moves them there? I wish that I could say we know the answer to those questions, but we don’t. The fact that we observe this patterning across species and systems suggests something fundamental to me. It’s probably not dependent on a specific growth factor or morphogen, but rather coupled to the subcellular changes necessary for a block-like epithelial cell to change shape in the first place.

MitoWorld: This is somewhat related to the previous question. Do you have any idea of how the mitochondria are held in position at the apical side of the cell?

Dr. Nelson: I’m not sure they’re actually held there, per se. We have some timelapse imaging data that suggest the mitochondria are fairly dynamic, moving along the apical-basal axis of the cell. It would be really cool to do a pulse-chase experiment with mitochondria to see how many persist on the apical side and how many move back and forth.

MitoWorld: You note an interesting balance between glycolysis and oxidative phosphorylation. Can you elaborate on that relationship?

Dr. Nelson: In many systems, it’s been reported that cells use either glycolysis or oxidative phosphorylation (oxphos) in lieu of the other. We don’t see that to be true for apical constriction, at least for the developing chicken lung where we conducted seahorse experiments. In that system, we found both increased oxphos and increased glycolysis in the regions of tissue undergoing apical constriction. So there’s certainly more to be learned about the energetics of apical constriction, and about how the cell budgets energy generated by oxphos versus glycolysis.

Reference

Lemma B, Rothstein M, Zhang P, Waas B, Kilwein M, Topiwala S, Zhang SX, Sudhakar A, Goodwin K, Gavis ER, Mallarino R, Kosmrlj A, Nelson CM (2026) Patterns of mitochondrial ATP predict tissue folding. Science Advances 12(17): eaee6175.

https://www.science.org/doi/full/10.1126/sciadv.aee6175

Shout out from www.MitoWorld.org to the Cell Metabolism team led by editor Salvatore Fabbiano for recognizing and facilitating our Mito-Cancer session at the Multifaceted Mitochondria Symposium (June 21-23, Glasgow). This included Cell Metabolism publishing our Commentary, Cancer as a window into mitochondrial biology.

For the Cell Metabolism Commentary and Symposium session, editor Fabbiano selected Gordon Freedman from Mitoworld and Kelsey Fisher-Wellman, PhD, Wake Forest University, to moderate a panel of experts including Thomas MacVicar, PhD, Professor of Mitochondrial Biology, University of Glasgow; Laura C. Greaves, PhD, Professor of Mitochondrial Biology, Newcastle University; Payam A. Gammage, PhD, Professor of Mitochondrial Biology, University of Glasgow; Stephen W. G. Tait, PhD, Professor of Cancer Biology, University of Glasgow.

This topic arose from questions we had at www.MitoWorld.org about the hundreds of millions of years cancers and tumors have had to evolve to import mitochondria, reprogram them, and make them more efficient to drive their growth. While these lines of research are simultaneously being investigated by cancer researchers and mitochondrial researchers, there has been very little cross-fertilization. This intersection of fields has much to teach us with regards to understanding cancer, mitochondria, and applications across not only mitochondrial disease, but also a broader base of diseases, dysfunctions and aging.

MitoWorld had been in the crossfire of conversations and contentions about whether mitochondria meaningfully move between cells or whether this reported behavior is anecdotal. It occurred to us that cancer is an evolutionary and physiological laboratory for this question, and others of mitochondrial plasticity. Given that mitochondria composition, state and function can differ from organ to organ, within organs, and across the range of cancers and tumors, we further wondered if this variation could be classified, stored in aggregate databases and be made of use to any community exploring mitochondria roles in disease, health and physiology. Hence, the birth of the Mito-Cancer Atlas Project, which aims to do just that.

We were not alone in this line of reasoning. Kelsey Fisher-Wellman, PhD, is at Wake Forest University and Atrium Health, where he runs his Cancer Metabolism Lab. Kelsey was well underway in building a mito-cancer atlas and typecasting mitochondrial differentiation looking for targeting windows.

“Nearly a decade ago, I started my laboratory on a simple premise: not all mitochondria are the same. Rather, mitochondria are specialized according to the physiological demands of their host cell. Before we ever made a measurement in cancer, we proved this concept using a first-of-its-kind physiological omics platform that we termed Mitochondrial Diagnostics. Our work has defined mitochondrial specialization across normal tissues and our discovery of exploitable mitochondrial vulnerabilities in AML provide proof-of-concept for a much larger vision. The Mito-Cancer Atlas is the logical next step: a systematic effort to map the physiological diversity of cancer mitochondria across all tumor types.” Kelsey Fisher-Wellman, PhD, Wake Forest University, Atrium Health

MitoWorld also joined forces with Phillip West, PhD, at the Jackson Laboratory, where he is Associate Professor, Co-Program Leader, JAX Cancer Center and Principal Investigator of the West Lab, which explores immune and inflammatory responses to genetic disorder and aging related diseases.

“I see The Jackson Laboratory as a natural strategic partner for the Atlas. JAX is supported by an NCI-designated Cancer Center and has the genetic model infrastructure, computational scale, and translational reach to move nominated targets from hypothesis to validated biology. My laboratory has spent the past decade studying how mitochondria impact immunity and inflammation in cancer and other aging-related diseases. Overall, our work argues that mitochondria are key to every aspect of cancer growth, metastasis, treatment toxicity, and long-term survivorship.” Phillip West, PhD, the Jackson Laboratory

To make a mitochondria-cancer typecasting and a mitochondrial atlas for this activity possible, MitoWorld and its collaborative platform, MITOS Global, formed a formal partnership with Heureka Labs, a Duke University spinout of Matthew Hirschey, PhD, where the Hirschey Lab investigates cellular nutrient sensing and metabolism using computational approaches to understand how metabolic pathways regulate health and disease.

“Modern cancer research labs generate biological data faster than they can process it. Insights sit buried in archives, experiments are repeated in silos, and findings aren’t structured for reuse across scientific networks. Institutions have turned to AI for a solution, but general-purpose language models are built to summarize what is already written, not to reason over what a lab has actually measured — and when pushed toward scientific inference, they aren’t able to identify the novel relationships in underexplored domains that drive impactful discoveries. That gap is exactly why Heureka exists. Our platform lets scientists run end-to-end projects — generating hypotheses, mining the literature, designing experiments, analyzing results, and interpreting findings — using models grounded in empirical biology for deeper insights.” Ioan Bolohan, CEO, Heureka Labs

MitoWorld, Fisher-Wellman and our Mito-Cancer Atlas project welcome mitochondria and cancer researchers interested in cataloging the richness of mitochondria states and plasticity in the range of cancers and tumors. We are currently working on a new website called the MitoCancer Frontier.

Previous Mito-Cancer www.MitoBlog posts are found here.

Proteostasis, the maintenance of a healthy, correctly folded protein network, is essential for cellular function. When mitochondrial proteins are damaged or misfolded, cells activate the mitochondrial unfolded protein response (UPRmt), a quality-control program that induces chaperones and proteases to help restore mitochondrial proteostasis. In simple model organisms, mild UPRmt activation has been linked to increased stress resistance and longer lifespan. A recent study led by María José Pérez and Michela Deleidi asked whether this response is equally protective in the human brain. The findings were published in Nature Neuroscience.

The team wondered how mitochondrial proteostasis is maintained in the aging human brain, how mitochondrial proteostasis is maintained in different human brain cell types and whether UPRmt activation has the same consequences across neurons and glia. Using human induced pluripotent stem cell-derived neurons, astrocytes and microglia, as well as neuronal-glial tricultures and microglia-containing brain organoids, they modeled mitochondrial proteotoxic stress in a human cellular context. Pharmacological inhibition of the mitochondrial protease LONP1 was used to induce mitochondrial protein misfolding and activate the UPRmt. This stress caused mitochondrial fragmentation and reduced mitochondrial membrane potential across cell types, but the downstream responses were markedly different.

The team found that mitochondrial stress profoundly altered human microglial metabolism, causing lipid remodeling, lipid-droplet accumulation and depletion of S-adenosylmethionine (SAM), a key metabolite involved in methylation and antioxidant defense. These changes were associated with DNA damage, inflammatory signaling and increased senescence. By contrast, neurons and astrocytes mounted more adaptive stress responses, whereas microglia showed impaired quality control and accumulated misfolded proteins.

The study shows that mitochondrial stress responses are highly cell-type specific in the human brain. Although the UPRmt can support proteostasis under some conditions, chronic activation in microglia can become maladaptive, promoting senescence and disrupting neuronal homeostasis. These results suggest that therapeutic strategies aimed at modulating mitochondrial stress responses will need to be carefully tuned by cell type, duration and disease context.

Statement of Significance by Drs. Pérez and Deleidi

Reports on the mitochondrial unfolded protein response, or UPRmt, have been contradictory, with protective effects in some settings and damaging effects in others. Our findings suggest that this depends, at least in part, on cellular context. Brain cells do not mount a uniform mitochondrial stress response: microglia responded earlier and more strongly than neurons, suggesting that they may act as key sensors of mitochondrial stress.

In microglia, however, sustained UPRmt activation was maladaptive, driving metabolic dysfunction, senescence and impaired communication with neurons and astrocytes. Microglia carrying a mitochondrial proteostasis defect were sufficient to induce senescence, reduce neuronal integrity and increase amyloid accumulation in brain assembloids. This signature overlapped with disease-associated microglial states found in aging and Alzheimer’s disease brain. These findings reveal how defects in mitochondrial quality control may contribute to neurodegeneration by altering the brain’s immune environment. They also highlight rare mitochondrial diseases as powerful models to uncover mechanisms relevant to common age-associated disorders, including Parkinson’s and Alzheimer’s disease. Overall, our study identifies microglial metabolism and mitochondrial proteostasis as potential therapeutic targets and underscores the need for cell-type-selective approaches rather than indiscriminate activation of mitochondrial stress pathways.

A Discussion with Drs. Pérez and Deleidi

MitoWorld: Can you give us an idea of where you might direct your future research to expand on the findings in this paper?

Authors:

One important direction will be to understand whether the mechanisms we identified in human microglia also operate in the context of specific neurodegenerative diseases. In this study, we found that chronic activation of the mitochondrial unfolded protein response can push microglia toward a senescent and inflammatory state. We now want to explore how this process interacts with disease-associated protein aggregates, such as α-synuclein in Parkinson’s disease or amyloid and tau pathology in Alzheimer’s disease.

We are also interested in defining whether the metabolic vulnerabilities we identified, particularly lipid remodeling and the SAM-polyamine axis, can be targeted to restore healthier microglial function. Ultimately, our goal is to understand whether correcting mitochondrial stress responses in microglia could help preserve neuronal homeostasis and slow disease progression.

MitoWorld: It is interesting that the mitochondria in different cell types had such different responses. Do you have any thoughts on why that might be? Is this just another case of how mitochondria are regulated by the nuclear genes?

Authors:

Yes, nuclear regulation is certainly part of the answer, but we think the explanation is broader. Mitochondria are deeply shaped by the identity, function and metabolic state of each cell type. Neurons, astrocytes and microglia have very different energetic demands, stress-response programs and roles within the brain. Therefore, the same mitochondrial stress can be interpreted very differently depending on the cellular context.

In our study, neurons and astrocytes appeared better able to activate adaptive compensatory pathways, whereas microglia showed a more maladaptive response, with impaired proteostasis, metabolic rewiring and senescence. This suggests that mitochondrial stress responses are not uniform across the brain. They are integrated with cell-type-specific transcriptional programs, metabolic wiring and immune functions.

MitoWorld: Each neurodegenerative disease features its own misfolded protein (e.g., Parkinson’s disease, a-synuclein; Huntington’s disease, huntingtin) and affects specific neurons. Could those be other examples of the type of cell-specific results of the UPR?

Authors:

Absolutely. One of the important lessons from our study is that proteostatic stress responses are highly cell-type specific. Different brain cells may have different thresholds for coping with misfolded proteins, and different diseases may expose vulnerabilities in distinct cellular populations.

In Parkinson’s disease, for example, dopaminergic neurons are particularly vulnerable, but microglia and astrocytes also shape how α-synuclein pathology spreads and how the tissue responds. Similarly, in Huntington’s disease or Alzheimer’s disease, the affected neurons and glial cells may engage different stress-response pathways depending on their metabolic state, proteostatic capacity and local environment. We think that understanding these cell-specific responses will be essential for designing therapies that do not simply activate or inhibit a pathway globally, but modulate it in the right cell type and at the right time.

MitoWorld: Do you have any speculation on the mechanism involved in the lipid remodeling?

Authors:

Our data suggest that lipid remodeling is not just a secondary consequence of mitochondrial stress, but part of the mechanism driving microglial dysfunction. When mitochondrial proteostasis is impaired, microglia appear to reorganize their lipid metabolism, leading to the accumulation of lipid droplets and changes in glycerophospholipid and glycerolipid pathways. One possibility is that lipid droplets initially form as a protective response to buffer damaged membranes, oxidative stress or excess fatty acids. However, when the stress is chronic, this adaptive response may become maladaptive. Lipid-droplet accumulation has been linked to impaired phagocytosis, increased inflammatory signaling and reduced cellular fitness in aging microglia. In our models, interfering with lipid-droplet formation reduced senescence markers, suggesting that lipid remodeling actively contributes to the senescent phenotype.

MitoWorld: As you note in the Discussion, your findings have significant implications for cancer treatments? Do you have plans to follow up on these possibilities?

Authors:

This is an important point. Some therapeutic strategies, including in oncology, aim to manipulate mitochondrial stress responses or proteostasis pathways. Our findings suggest that these approaches may have cell-type-specific effects that need to be carefully considered. In particular, chronic activation of mitochondrial stress responses in immune cells could potentially promote senescence or inflammatory dysfunction. Our main focus remains neurodegeneration, but we think the broader implication is that mitochondrial stress pathways should be studied in a tissue- and cell-type-specific manner. It will be important to understand when activation of the UPRmt is beneficial and when it becomes maladaptive. This principle could be relevant not only for brain diseases, but also for cancer and other age-associated conditions in which senescence, inflammation and mitochondrial dysfunction intersect.

MitoWorld: Can you tell us how you came to be interested in mitochondria?

Authors:

Our interest in mitochondria came from trying to understand why certain brain cells are especially vulnerable in neurodegenerative diseases. Mitochondria sit at the intersection of several processes that are central to these diseases: energy metabolism, inflammation, protein quality control, oxidative stress and cellular aging. For our group, mitochondria became particularly interesting because they provide a way to connect rare genetic disorders with broader mechanisms of neurodegeneration. Studying defects in mitochondrial proteostasis can reveal fundamental biological pathways that may also be relevant to common age-associated diseases. Over time, this led us to focus not only on neurons, but also on glial cells, especially microglia, and to ask how mitochondrial stress in these cells affects the entire brain environment.

Reference

Perez J MJ, Lam A, Weissleder C, Bertoli F, Raji H, Bosch M, Nemazanyy I, Kalb S, Kehili M, Hirschberg I, Brunetti D, Heckenbach I, Scheibye-Knudsen M, Deleidi M (2026) The mitochondrial unfolded protein response in human microglia disrupts neuronal–glial communication and promotes senescence. Nature Neuroscience https://doi.org/10.1038/s41593-026-02320-1.

Chemotherapy resistance accounts for more than 80% of cancer deaths, and so, preventing its development is a significant challenge in cancer treatment. Resistance comes from multiple sources. Some are related to the cancer cells themselves, and others are in reaction to the therapy. New ways to prevent the development of resistance are urgently needed to improve patient outcomes.

Recently, a multi-institute research team, led by Emma M. Kerr of Queen’s University Belfast, sought to better understand the cellular mechanisms related to resistance. To do this, they studied the cellular effects of chemotherapy in colorectal cancer. Their findings were published in a paper in Nature Metabolism.

To promote tumor progression, cancer cells reprogram cell energetics. Thus, the Kerr team chose to examine therapy resistance in colorectal cancer. They wanted to determine how mitochondria facilitate the acute stress response to 5-fluorouracil (5FU) in cells that survived treatment. That cancer is commonly treated with 5FU, but the effects are not fully understood. 5FU causes great metabolic stress to cells, and so, the research team examined its effects on mitochondria because of their deep involvement in cell metabolism.

Their results show that 5FU has multiple effects on mitochondria. Specifically, 5FU promotes mitochondrial adaptation at multiple levels. It changes the number, the communication and the activity of mitochondria, all of which mean that the cell can survive the metabolic stress caused by the drug. It does not inhibit complex I, it increases it’s activity, and the activity of the mitohcondria, and cell metabolism in general to delay tumor growth and prolong cell survival in preclinical models. They also found that oxidative metabolism signatures might predict the response to 5FU therapy.

This study enhances our understanding of how resistance to 5FU is driven by a coordinated mitochondrial response, but this can be blocked to deepen responses to 5FU. The increase mitochondrial activity was key to the ability of cancer cells to survive treatment with 5FU. Importantly, the findings suggest that this therapy can be used as part of combination therapy for colorectal cancer.

A Statement of Significance by Dr. Kerr.

Our work establishes mitochondrial plasticity as a central mechanism of acute chemotherapy tolerance in colorectal cancer. We show that, in response to 5FU-induced metabolic stress, cancer cells increase mitochondrial biogenesis, organisiation and respiratory activity to restore pyrimidine balance. This adaptation reveals a previously unrecognised mechanism of treatment tolerance and creates a targetable vulnerability that could inform patient stratification and rational combination therapies.

A Conversation with Dr. Kerr and Dr. Shaw

MitoWorld: Can you give us an idea of the direction your research might take to further your findings in the current paper?

EK: Our next step is to investigate how mitochondrial, and more broadly metabolic, plasticity influence treatment response and resistance in metastatic colorectal cancer. We are particularly interested in how the distinct environments of different metastatic sites reshape tumour metabolism, alter mitochondrial adaptation and ultimately determine sensitivity to 5FU-based therapy.

AS: From a fundamental biology standpoint, I’m particularly keen to map the precise molecular pathways that bring about the acute burst in mitochondrial biogenesis and structural reorganization that we observe. Chemotherapy-induced metabolic disruption acts as a powerful stress test. By studying how mtDNA copy number, organelle turnover, and quality control mechanisms are regulated during acute 5FU survival, we can uncover basic principles of mitochondrial plasticity that dictate how mammalian cells endure severe metabolic insults.

MitoWorld: Do you think the increased need for mitochondrial activity is related to the need for more energy production or is there a more complex mechanism at work?

EK: We think the mechanism is more complex than simply producing additional energy. 5FU disrupts pyrimidine balance, and our data indicate that surviving cancer cells increase mitochondrial activity to support UCK2-dependent uridine salvage and the restoration of nucleotide pools. Because this process involves several ATP-dependent phosphorylation steps, increased mitochondrial capacity may help sustain the response. However, mitochondria are likely supporting a broader metabolic programme, rather than acting solely as a source of ATP.

AS: I completely agree that it goes far beyond ATP generation. Mitochondria are fundamental metabolic integrators. When 5FU disrupts pyrimidine synthesis, mitochondria respond not just by ramping up bioenergetics, but by dynamically rewiring metabolic fluxes to feed nucleotide recovery and maintain redox balance. It highlights that mitochondria act as dynamic homeostatic sensors, they adapt their structure and function under extreme environmental stress to prioritize critical cellular salvage pathways over baseline energy production.

MitoWorld: This research has clear clinical implications. You note several in the Discussion. Do you plan to follow up with some of these?

EK: Yes. Our immediate priority is to translate these findings towards clinical testing by evaluating drugs that can disrupt the mitochondrial adaptations induced by 5FU. This could include repurposing existing medicines, as well as testing newer metabolism-targeted agents in combination with chemotherapy. In parallel, we want to refine mitochondrial activity signatures as biomarkers, so that future trials can focus on patients whose tumours are most likely to benefit from these combinations.

AS: Yes, and what excites me about the translational side is that targeting these adaptive mechanisms relies on dissecting fundamental mitochondrial biology. By understanding the specific mechanisms of mitochondrial biogenesis and respiratory reliance that surviving cells depend on, we can identify and exploit precise metabolic vulnerabilities in patients.

MitoWorld: Your work here was specific to colorectal cancer and 5FU. Can you speculate on whether your findings might have applications for other cancers? For example, 5FU is also commonly used to treat actinic keratosis and superficial basal cell carcinomas.

EK: Although our study focused on colorectal cancer and 5FU, the mechanism we identified appears to be linked more broadly to thymidylate synthase inhibition and the resulting pyrimidine stress, rather than to colorectal cancer alone. More than five million patients each year receive thymidylate synthase–targeting treatments, including fluoropyrimidines across gastrointestinal and other cancers, and antifolates such as pemetrexed in lung cancer. In our study, several TS-targeting drugs triggered similar mitochondrial adaptation across different cancer models, including lung cancer cells, suggesting that mitochondrial plasticity may be a wider mechanism of treatment tolerance. It is therefore also plausible that related responses could occur in conditions treated with topical 5FU, such as actinic keratosis or superficial basal cell carcinoma, although the route of drug delivery and tissue environment are very different and would need to be studied directly.

AS: It’s a fascinating prospect. Mitochondria possess a core, conserved toolkit for responding to extreme physiological pressure. Whether a cell is an exercising muscle fiber adjusting to oxygen debt, a neuron undergoing mitochondrial quality control under neurodegenerative stress, or a cancer cell enduring high-dose antimetabolite therapy, the underlying rules of mitochondrial adaptation are widely conserved! Whether these findings translate to other cancers in the context TS targeting therapies is an exciting area of future discovery for sure!

MitoWorld: Mitochondria are such deceptively simple organelles with an extraordinary range of activities. Can you comment on how they have evolved to be so critical in so many diseases?

EK: Mitochondria are involved in so many of the processes that shape how a cell behaves that it is not surprising they are linked to such a wide range of diseases. They do far more than generate energy, helping to coordinate metabolism, redox balance, signalling, immunity and the decisions that determine whether a cell survives or dies.

What makes mitochondria especially interesting is how adaptable they are. In cancer, tumour cells can take advantage of that flexibility to keep growing, cope with difficult environments and survive treatment. In other diseases, when those same mitochondrial processes go wrong, they can contribute to inflammation, degeneration or metabolic dysfunction. Their importance comes from the fact that mitochondria do not just support what a cell is doing; they help determine how that cell behaves.

That is why it is so important that we continue to study mitochondria in the right biological context. Advances in imaging, metabolic profiling and single-cell technologies are only now allowing us to appreciate how dynamic and context-dependent their roles really are. At the same time, disease-specific models, like genetically engineered mouse models used for CRC, let us examine mitochondrial behaviour within complex tumours that retain their surrounding tissue and immune environment. The more closely we study mitochondria in these realistic settings, the clearer it becomes that they are not simply affected by disease – they can actively shape how disease develops, progresses and responds to treatment.

AS: Their central role in disease stems directly from their evolutionary origin as endosymbionts and their function as primary metabolic and signaling integrators. Rather than serving merely as static ‘powerhouses,’ mitochondria evolved to sense physiological cues and coordinate crucial cell fate decisions as Emma mentioned. Given such broad control over cellular survival, their widespread involvement across disease indications is entirely expected.”

MitoWorld: How did you come to be interested in the involvement of mitochondria in cancer?

EK: My interest in mitochondria grew from a broader question: how do cancer cells survive extreme stress, and can we use that to expose new therapeutic weaknesses?

During my PhD, I studied how to increase cancer cell death, both through mitochondrial dependent, and independent, apoptosis. In my postdoctoral work I then explored the other side of that biology: how cells survive very high levels of KRAS-driven stress. We found that cells with the highest KRAS activity had fundamentally reprogrammed their mitochondria.

This context specificity really shaped the direction of my own lab. Mitochondria have this Janus-like role in controlling both life and death, and both sides create vulnerabilities we can exploit. Our current work asks how mitochondrial plasticity supports treatment tolerance and how we can turn that adaptation against the tumour.

AS: My interest in mitochondria stems from my early background in muscle biology and exercise physiology, where I became fascinated by how dynamically these organelles adjust to metabolic demand. When searching for PhD opportunities, I was struck by how many distinct human pathologies, from neurodegeneration to metabolic disorders,trace back to mitochondrial dysfunction. My PhD focused on unravelling a critical mitochondrial quality control pathway dysregulated in Parkinson’s disease, but my postdoctoral research shifted toward oncology, examining mitochondrial DNA copy number regulation in cancer.

What continues to stimulate my curiosity is a desire to understand the fundamental, basic biology of mitochondria more broadly, rather than viewing them strictly through the lens of a single disease. However, extreme pathological states, such as a cancer cell enduring high-dose chemotherapy stress, provide an unparalleled experimental window. They push mitochondrial plasticity to the limit, allowing us to uncover core mechanisms of organelle dynamics and stress tolerance that might otherwise remain hidden in homeostatic tissue.

Reference

Moss DY, Brown CN, Shaw AM, … Kerr EM (2026) Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer. Nat Metab.

https://doi.org/10.1038/s42255-026-01578-w

The importance of human biome to our overall health is well-established. Disruptions in the flora and fauna of the human gut can cause serious problems. The most common of these is irritable bowel syndrome (IBS), but the associated disorders of small intestinal bacterial overgrowth (SIBO), intestinal methanogen overgrowth (IMO), and intestinal sulfide overproduction (ISO) are associated with IBS. Patients with these conditions have higher levels of breath hydrogen sulfide or methane, and higher bacterial colony counts, but they are not well defined.

A study led by Mark Pimentel and Juliana de Freitas Germano sought to bring more clarity to these disorders. The study was recently published in mSystems. The team examined gene transcriptomics of biopsies from several different groups. The groups included the small bowel of patients with IMO, ISO, and SIBO and from rats who were gavaged with bacteria that produce hydrogen sulfide.

Interestingly, each condition yielded unique results. For example, the genes linked to H₂S toxicity (e.g., electron transport chain and redox balance genes) of ISO patients were significantly affected, but the gene expression patterns of those with IMO and SIBO were affected much less. Results from the rat studies were similar to the ISO findings (e.g., dysregulation of mitochondrial respiration, redox balance, water homeostasis, immune response, and gut motility). Similar gavages with non-sulfide bacteria had no effect.

This study offers new insights into these disorders. The findings suggest that ISO symptoms are associated with bacterial H₂S effects. Furthermore, it emphasizes the need for therapeutic strategies targeted specifically to each condition.

A Statement of Significance by Dr. Pimentel:

Our transcriptomic profiling study of small bowel biopsies revealed potential mechanisms underlying the pathophysiology of ISO, IMO, and SIBO and suggested that these are three distinct gut disorders that should be treated differently, with special attention to ISO and its broad effects on gene expression.

A Conversation with Dr. Pimentel:

MitoWorld: Can you give us an idea of how you will continue with this line of research?

Dr. Pimentel: We have expanded our use of omics techniques to better understand alterations in the small bowel ecology and environment associated with SIBO, IMO, and ISO, to improve not only diagnosis but also treatment.

MitoWorld: H₂S controls an amazing array of activities. The involvement of mitochondria in its regulation is yet another aspect of cell biology moderated by these organelles. Were you surprised by this connection?

Dr. Pimentel Even though we know that H₂S affects mitochondria, we wanted to explore whether this could be identified by classifying groups based on their H₂S levels in exhaled breath. We were surprised that changes in mitochondrial biological processes, such as those related to mitochondrial ATP synthesis, were already happening at 1.5 ppm of H₂S.

MitoWorld: Do you have any idea of what causes the dysregulation of the organisms that cause these disorders?

Dr. Pimentel: Dysregulation of organisms causing ISO, IMO, and SIBO can occur when the intestine loses its ability to clear them. In many patients, that loss begins after an episode of food poisoning, which triggers an autoimmune response in the gut’s motility system. Once gut motility is impaired, these organisms can persist or thrive where they shouldn’t, leading to ISO, IMO, and/or SIBO.

MitoWorld: You noted that further studies with larger sample sizes might identify the more important genes that are affected. Do you have any leading candidates?

Dr. Pimentel: I will focus specifically on ISO (no co-occurrence of SIBO and/or IMO) since it showed broad changes in gene expression. We analyzed small bowel transcriptomics from subjects with a minimum of 1.5 ppm but below 2.0 ppm of exhaled H₂S (n=16) and those with ≥ 2.0 ppm of exhaled H₂S (n=12), separately. When comparing these groups against subjects without ISO/SIBO/IMO (n=19), both comparisons showed, for example, downregulation in SLC7A11, which is involved in redox balance and ferroptosis regulation, and IL1B, which encodes a proinflammatory cytokine. When these H₂S groups were combined (n=28), these changes were still there and more significant. Also, we identified dysregulation of several mitochondrial-associated genes, upregulation of CYP1A1 (redox balance), downregulation of CTH (endogenous H₂S production), and upregulation of SST (gut motility and pain) in one of the H₂S subgroups and in the combined group comparisons. Thus, we strongly believe that further studies with larger sample sizes will continue to show redox balance-, endogenous H₂S production-, gut motility and pain- and mitochondrial-associated mechanisms and genes as important findings in ISO, independent of SIBO and/or IMO.

MitoWorld: Are there any interactions among the various sulfide, methanogenic, and other organisms that might complicate the situation?

Dr. Pimentel: In terms of transcriptomics, most differentially expressed genes and significant changes were found in ISO when combined with SIBO and/or IMO. These findings may suggest that interactions among the organisms associated with these different disorders are affecting the small bowel tissue more deeply. In other words, most changes were found in ISO, and we believe this is the leading cause of alterations in gene expression; however, these alterations can be intensified when co-occurring with SIBO and/or IMO. We haven’t proved that hypothesis in this manuscript, but this is within the scope of our future investigations.

MitoWorld: Do you see any clinical applications of your findings, and might you follow up on those?

Dr. Pimentel: Our findings demonstrate that SIBO, IMO, and ISO are distinct disorders that should be managed differently in clinical practice. The most pronounced transcriptomic alterations were observed in ISO, which is also usually associated with greater symptom severity, including diarrhea and urgency. These findings may contribute to the development of targeted or combination therapies for small bowel disorders, representing an important direction for future research.

Reference

de Freitas Germano J, Leite G, Villanueva-Millan MJ, Brimberry D, Rashid M, Hosseini A, Flor D, Bogatyrev S, Morales W, Weitsman S, Sanchez M, … Pimentel M (2026) Transcriptomics profiles in intestinal sulfide overproduction, small intestinal bacterial overgrowth, and intestinal methanogen overgrowth. mSystems 11: e00458-26.

https://doi.org/10.1128/msystems.00458-26