Mitochondrial DNA Mutations and Aging

In a paper published in Science,¹ Samir M. Parikh and an inter-institute research team explored the relationships among mitochondrial DNA (mtDNA) mutations, acute injuries, and chronic damage to the kidney. They found that the injuries result in mutations that hinder the mitochondria’s key activities and leave the organ more susceptible to future damage. Importantly, they found that this damage was amenable to metabolic treatment.

Mutations to mtDNA have been implicated as a driver of aging. The mitochondrial genome is much smaller than the nuclear genome. However, each cell contains hundreds to a thousand or more mitochondria, and each mitochondrion contains two to 10 copies of the mtDNA. Interestingly, mutations to mtDNA accumulate with aging, and that accumulation accelerates after age 70. The mutations to some but not all copies of the mtDNA in each mitochondrion result in differences in those genomes. This is called heteroplasmy.

The team used a mouse model for acute and chronic injuries to kidneys to examine the effects of mtDNA mutations. They found that the mutations accumulate and that they reduce gene expression, oxidative metabolism, and resistance to oxidative injury. Exogenous supplies of adenosine, but not other nucleosides, improved the function of the injured kidneys. Further studies identified loss of the key enzyme adenylate kinase 4, encoded in the nuclear genome, as the reason for the loss of ATP and the ability of adenosine to improve outcomes.

When they examined a large human cohort of 370,000 individuals from the UK biobank, they found that mtDNA mutations represented a risk factor for future acute injury and associated with the severity of chronic kidney disease. These results confirmed the association between mtDNA mutation burden and kidney injury.

These findings also confirm the kidney as an excellent model for the study of aging. Finally, they suggest that injuries to other organs, such as stroke and myocardial infarction, might be influenced by the effects of accumulating mtDNA mutations.

Conversation with Dr. Parikh and first author Dr. Huihui Haung

MitoWorld: What is the next likely goal in your research to follow up on this work?

SMP and HH: There are so many different directions to take this work, and they’re all interesting! On the translational side, does the relationship between mtDNA mutation burden and kidney disease hold in other human cohorts? More fundamentally, what mechanisms does a cell employ to monitor the fidelity of its mtDNA? Is it just overall oxidative function, or something more specific? Do cells in other organs composed of long-lived cells endowed with a high mitochondrial content also exhibit time and injury-dependent mtDNA mutations?

MitoWorld: There are so many copies of the mtDNA in each cell that it seems hard to understand how mutations to some of them can cause trouble. Do you have any speculation on what the threshold is for those mutations to be a problem?

SMP and HH: There are a few possibilities. First, the heteroplasmic single-nucleotide variants that are a focus of the manuscript represent one kind of mtDNA damage. Other assays largely relegated to the supplementary materials accompanying the paper demonstrate the rapid appearance and persistence of more profound changes to the mtDNA, such as indels. Second, we found that artificially introducing heteroplasmic mtDNA mutations by compromising the 3-5′ exonuclease activity of POLG sufficed to reduce oxidative function in renal tubular epithelial cells. Whether these changes affect tRNA function or subunits of the electron transport chain, or both, remains to be determined. Finally, in the cellular and mouse model data, we analyzed heteroplasmy without a threshold, but because the human data have so many orders of magnitude higher replicates per group, we were able to employ a more stringent variant allele frequency cutoff of 5%.

MitoWorld: Interestingly, the damage in your model was to a nuclear gene. How do you see the mtDNA mutations related to that enzyme?

SMP and HH: We do not yet have direct evidence that the enzyme AK4 regulates mtDNA mutations. However, we know that communication between the mitochondrial and nuclear genomes is essential to maintain mtDNA heteroplasmy within a safe threshold. AK4 is a nuclear-encoded mitochondrial protein and a key enzyme that regulates cellular ATP levels. Its expression is highly responsive to mitochondrial DNA damage. We speculate that AK4 may serve as a bridge or sensor that transmits deleterious mitochondrial signals to the nucleus, coordinating energy balance and mitochondrial fate. Further studies are needed to test this hypothesis.

MitoWorld: Damaged mitochondria have been implicated in aging and your current work also suggests that. What mechanisms might be involved? Is it just the slow deterioration of energy production or another mechanism?

SMP and HH: This is a really interesting question. Recent exciting work also conducted in the UK Biobank resource suggests that the nucleus has an important role in determining the burden of mtDNA mutations over a lifetime.² The nuclear genes they implicated through a GWAS analysis were either the same or highly related to the ones we arrived at experimentally. The notion of a cell’s battery running down with age is intuitive and appealing. It is also possible that there is gain of toxic function as the mitochondrial code degrades. More work is needed to dissect among these possibilities.

MitoWorld: Can you envision how reducing mtDNA heteroplasmy might slow the processes of aging?

SMP and HH: Restoring the mitochondrial code may itself improve the oxidative function of the cell’s organelle. One could also imagine that the cellular processes involved in balancing the cell’s complement of mitochondria—namely the balance between mitochondrial biogenesis and mitochondrial clearance through mitophagy and the lysosome—wind up having multiple beneficial effects on overall cellular function.

MitoWorld: What about mitochondria interested you in the first place?

SMP and HH: As your readers appreciate, mitochondria are weird in many wonderful ways. Their membranes are composed of different lipids, their proteins start with a uniquely modified N-terminal amino acid, and the mtDNA genome lacks introns and the code to generate the vast majority of proteins that make up mitochondria, but exists in variable and polyploid amounts. The generation and dissolution of mitochondrial mass can be uncoupled entirely from cellular replication, and even the physical structure and networked appearance of mitochondria within cells are highly dynamic. Our bodies’ reliance on these weird organelles is clear from genetic experiments of nature.

The human data on monogenic mitochondrial syndromes are clear that kidney health is frequently impaired. It’s very easy to visualize mechanical work, such as skeletal or cardiac muscle contraction, requiring lots of ATP. But the tubular epithelium in the kidney is doing an enormous amount of chemical work. It might surprise the readers to know that, in humans, this specialized epithelium is responsible for the active transport of more than one pound of sodium back into the body every single day, atom-by-atom, against powerful electrochemical gradients. That’s more than 10e25 cations being pushed “uphill” back into the body from the crude filtrate every day. This apparatus is so exquisitely tuned that even a reduction to 10e24 sodium atoms would be lethal in a matter of minutes.

References

¹ Huang H, Wang Y, Zsengeller ZK, Gorham JM, Vemireddy V, Clark AJ, Pan H, Dreyfuss JM, Jotwani V, Shlipak MG, Sarnak MJ, Parikh CR, Thiessen-Philbrook H, Katz R, Waikar SS, Lake NJ, Lek M, Shi W, Puiu D, Hong YS, Seidman JG, Arking DE, Parikh SM (2025) Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations. Science 390: 164–172.

² Gupta R, Kanai M, Durham TJ, Tsuo K, McCoy JG, Kotrys AV, Zhou W, Chinnery PF, Karczewski KJ, Calvo SE, Neale BM (2023) Nuclear genetic control of mtDNA copy number and heteroplasmy in humans. Nature 620: 839–848.

A Divided Community

In a September 2025 Viewpoint published in Nature Metabolism entitled “Mitochondria Transfer,” the editors noted, “. . . the topic continues to be met with skepticism.” As a result, the journal asked nine mitochondrial biologists to share their personal views on intercellular mitochondria transfer. There was little new here.

Their responses amounted to yes, no, and maybe. Many questions loom for otherwise promising results. What are the mechanisms and consequences of this process? If mitochondria do move between cells endogenously, when they arrive in another cell, do they resume their normal functions? Does the transfer of a relatively small number of mitochondria have the power to rescue a cell that is under bioenergetic stress?

At MitoWorld, we know most of the Viewpoint respondents, and we know the gulf between them. By kicking off debate, Nature Metabolism has started a process that we hope can mature from rhetoric to a more evidence-based picture of the efficacy of mitochondrial transfer and transplantation. Across the globe, investigations are underway in both categories. Given the limited mechanistic understanding of this process, it is surprising that mitochondrial transplantation is now a not uncommon medical intervention and remains a tantalizing subject of research and development in a variety of biotech companies.

First Step: Nomenclature

In all of this, there is a blurring of terminology. In January, Jon Brestoff and Keshav Singh, et al. published “Recommendations for mitochondria transfer and transplantation nomenclature and characterization,” also in Nature Metabolism. What is clear in their paper’s title is the notion of i) transfer being endogenous, part of an intrinsic biological mechanism and ii) transplantation, the act of deliberately introducing mitochondria into organs, tissues, and cells being exogenous. Over 30 researchers participated in what was a laudable effort to explore agreed-upon naming, processes, and explanatory conventions. While the consensus statement and an agreement for an International Committee on Mitochondria Transfer and Transplantation Nomenclature (ICMTTN) represents an important step forward, notable disagreements persist. Foremost among the complications related to mitochondrial transfer and transplantation relates to the unknown fate of any mtDNA harbored by incoming organelles.

Second Step: Conference

MitoWorld found itself in the middle of this controversy when it was asked to help with the first Mitochondrial Transplantation Conference. Held in April at Hofstra University, the event was organized by Northwell Health and led by Lance Becker. It featured a mix of compelling medical intervention talks and video for failing hearts (James McCully), treatment for stroke victims (Melanie Walker), and other resuscitation experiments with animals (Lance Becker). MitoWorld assisted in having endogenous transfer represented (Jonathan Brestoff). In all of this, there was excitement but also apprehension that parents of children and adults with mitochondrial genetic diseases will be given false hope for near-term treatments. Several drug developers were present, as were patient groups. It is likely some form of transplantation organization will emerge from that meeting.

Deeper Dive—Transfer and Transplantation

Given the lack of evidence-based dialogue, MitoWorld reached out to the Viewpoint respondents who are actively doing work in both categories. Yasemin Sancak, The Sancak Lab, University of Washington Pharmacology, and Rubén Quintana-Cabrera, Neurometabolism and Mitochondrial Dynamics Lab, Instituto Cajal, CSIC responded to MitoWorld.

MitoWorld: Why do you think there is such a controversy about mitochondria transfer and transplant? 

Sancak: Transfer of mitochondria between cells is shown in different organisms and systems, and although this is relatively novel finding, it is widely accepted in the field. However, mitochondria transplantation attracts skepticism. In my opinion, the controversy stems from the expectation that, for mitochondrial transplantation to work as intended, the transplanted mitochondria should successfully incorporate into the host tissue in large numbers and maybe survive there for a long time, integrate into the donor tissue, and restore mitochondrial function and tissue health. Currently, the evidence of this happening is limited, and mechanisms of mitochondrial entry and survival are not well understood. But we also cannot ignore the exciting data that show the utility of mitochondrial transplantation in the clinic. Until we understand the molecular details and mechanisms of this process, the controversy is likely to continue. The field needs more preclinical and clinical research to understand mechanisms of therapeutic benefit and to establish clinical guidelines.

Quintana-Cabrera: These are quite novel concepts, now widely accepted by the scientific community after solid data in different cells and tissues. My perception is that both general and even specialized audiences are mostly focused on the incorporation of healthy mitochondria from neighboring cells or tissues to enhance mitochondrial activity in the compromised recipient cell. However, we should not overlook the transfer of damaged mitochondria, which may also benefit a cell by enabling their elimination through surrogate degradation in neighboring cells. Regarding transplants, the apparent controversy mainly concerns the injection of isolated mitochondria. Transplants using donor cells, such as mesenchymal stem cells or mitochondria encapsulated in vesicles or artificial membranes are viewed as able to better withstand the extracellular environment and the journey through the body to the target tissue. However, those advocating for transplants of isolated mitochondria need to standardize the approaches and to clarify how mitochondria survive outside the cell, influence inflammation, and integrate into recipient cells, or if they can take over native mitochondrial function in the long term.

MitoWorld: What may convince you that transfer happens naturally and/or that transplantation has effects? 

Sancak: Many animal and cell culture studies show that mitochondrial transfer happens naturally, and this process is likely to serve different functions. Mitochondrial transplantation research in a pre-clinical setting mostly shows positive outcomes, but the long-term benefits of mitochondrial transplantation are not addressed. A small number of human studies show clinical benefit, but these are mostly feasibility and safety studies that were conducted with a small number of patients. One promising common finding from human studies so far is that mitochondrial transplantation does not seem to have any adverse effects and is generally considered to be safe. I think this is very promising and should open the door to bigger clinical trials. Ultimately, well-controlled clinical trials are needed to determine if mitochondrial transplantation will work for a disease of interest and what long term effects will be.

Quintana-Cabrera: A growing body of evidence demonstrates the natural occurrence of different types of transfer, mediated by tunneling nanotubes, microvesicles, or naked mitochondria, across various tissues and both in physiology and pathology. This is leading the scientific community to accept mitochondrial transfer as a naturally occurring event.

Of course, this is still a young field, and existing gaps need to be addressed by thoroughly evaluating the various dimensions of mitochondrial transfer. For example, further progress is needed in the assessment of intercellular communication mechanisms, such as tunneling nanotubes, which contribute to mitochondrial transfer but are technically challenging to study in vivo. Transplantation can produce meaningful effects, at least in the short term, depending on the delivery method, dosage, and source of mitochondria. Additional manipulations may enhance mitochondrial integration, modulate immune responses, or improve targeting to the appropriate tissue. However, it remains essential to understand how transplanted mitochondria interact with a much larger population of resident ones and to characterize both the short- and long-term effects of transplantation. This knowledge will help determine which strategies are truly beneficial. Such benefits may arise from whole mitochondria, their components, or even from transient cellular responses triggered by the presence of exogenous mitochondria.

MitoWorld: What do you say to those who contend that transplantation, at best, is a reaction to the presence of transplanted mitochondria, not that transplanted mitochondria are functionally integrated into recipient cells?

Sancak: This is an important question that highlights the significance of understanding what happens at the molecular level once the external mitochondria are delivered to the recipient cells. Most animal experiments show that the transplanted mitochondria must be functional to provide a positive outcome in the recipient cells. This suggests that the recipient cells’ reaction to presence of transplanted mitochondria is not the whole story, and transplanted mitochondria function is important. I think it is more likely that both mechanisms will play a role, and depending on the disease, transplantation method, and recipient cell, one mechanism may play a more prominent role than the other.

Quintana: This is a critical question that indeed needs clarification. Are transplanted mitochondria directly restoring function, or are they instead exerting indirect effects that still benefit the recipient cell or tissue? The latter could involve activation of stress-response pathways that partially restore homeostasis. Again, the source or method to deliver mitochondria may be key to what response is engaged, and the functional integration of mitochondria may not always be necessary to explain beneficial outcomes. Depending on the kind of transfer, whole mitochondria, or at least mitochondrial DNA, may escape degradation and integrate into the acceptor cell. Even in this scenario, we still need to assess whether and how their contribution reconfigures the native mitochondrial content, and what other events may occur in parallel.

MitoWorld: What does your research from actual cases tell you about what the transplanted mitochondria are actually doing? 

Sancak: The transplantation studies I was involved in were focused on safety, and no clinical outcomes other than safety were monitored rigorously. What I can say is that mitochondrial transplantation appears safe in every system tested, which makes it more appealing to pursue as a potential therapeutic intervention. We still need to systematically investigate which mitochondrial functions are the most important.

Quintana: We observe spontaneous mitochondrial transfer in the nervous system, particularly at neuron-glia connections, in both healthy tissue and in pathological contexts, such as glioblastoma. The latter represents another dimension of transfer, where cancer-neural connectivity and mitochondrial exchange are emerging as key factors in cancer progression. We see that, in physiological contexts, transfer occurs spontaneously and is regulated by specific molecular players involved in intercellular communication and dynamics. Notably, we observe that different ways of transfer or mitochondrial acquisition serve to reconfigure the mitochondrial signature and metabolism in the nervous system and glioblastomas, with the potential to modulate their physiology and offer new venues for therapeutic interventions.

Recommendation

Having been involved in this topic for some time, MitoWorld has discussed a simple step toward moving from debate to a methodology to review what is being discovered in mitochondrial transfer (endogenous) and what is being performed in mitochondrial transplantation (exogenous). Here are the suggestions and more are welcome from the community.

1. Establish a working group to track developments

As Brestoff, Keshav, et al. did with nomenclature, MitoWorld suggests the establishment of an agreed-upon tracking system for transfer and transplantation activity. This could be a formal registry, an inventory, or catalog. It will include common terminology and naming of activity, methods, collection, evidence, results, conclusions, and recommendations. We are asking a number of researchers to help in this process.

2. AI review of literature and associated data

MitoWorld has a relationship with Heureka Labs, developed in part by mitochondrial and metabolic researcher and AI specialist Matthew Hirschey, PhD (Duke University School of Medicine). Heureka will develop an initial approach to use AI to index past research for categories of activity and to develop data standards for analyzing and synthesizing data and processes.

3. Basic science and the phenomenology of mitochondria

There is still much to learn about our endosymbionts, the mitochondria, along with their DNA, and the complex mitonuclear system. Mitochondria have suffered years of obscurity in many forms of research and medicine. They have been typecast as the powerhouse of the cell. mtDNA is just beginning to be a larger topic, with the first conference on the subject having been held this summer in Nashville, Mechanisms of Mitochondrial DNA Mutation and Repair. We would like to see the still poorly understood mechanisms of mitochondrial biology become more central to funding agencies around the world, as it is increasingly apparent that mitochondria, as the hubs of metabolism, are central to the health of our cells.

A collective effort across the mitochondrial research and clinical communities has sought to play down the “powerhouse of the cell” phrase as the sole description of mitochondria and, instead, to elevate the amazing multiplicity of mitochondrial functions. Top among those functions is mitochondrial signaling. The leaders in the signaling field will be gathering at the Keystone “Mitochondria Signaling in Physiology and Disease Symposium,” Feb 09–12, 2026, at the Keystone Resort, Keystone, Colorado in the U.S, whose keynote speaker is Anu Suomalainen Wartiovaara, University of Helsinki, presenting “Lessons Learned from Patients with Mitochondria Mutations for Physiology and Diseases.” [Conference Flyer]

Scientific organizers, Navdeep Chandel, Northwestern University Feinberg School of Medicine, and Aleksandra Trifunovic (video), Institute for Mitochondrial Diseases and Aging, University of Cologne, among the most published on the topic, have brought together a very strong group of international speakers to present findings and stimulate dialog.  Among them is José Antonio (Tonio) Enríquez, Professor and Group Leader of the “Functional Genetics of the Oxidative Phosphorylation System (GENOXPHOS)” Laboratory at the Spanish National Center for Cardiovascular Research (CNIC) in Madrid, Spain.

Because of Tonio’s expertise in mitochondrial bioenergetics, oxidative phosphorylation (OXPHOS) and mitochondrial signaling and communication, MitoWorld asked him to answer a few questions about mitochondrial signaling and its significance to build the platform for understanding mitochondria more completely.

MitoWorld: What is the significance of this conference in terms of content, collaborations and the field of mitochondrial signaling?

Enríquez: This Keystone conference represents a pivotal moment in mitochondrial research, marking the formal recognition of mitochondria as central signaling hubs rather than mere energy factories. The conference, organized by Navdeep Chandel and Aleksandra Trifunovic, brings together field leaders who have fundamentally reshaped our understanding of mitochondrial biology over the past 25 years.

MitoWorld: Why is the conference important to do you individually? Can you introduce your area that relates to signaling?

Enríquez: My research area directly relates to signaling through the study of metabolic channeling and respiratory supercomplex assembly. These structures are not merely efficient ATP production units. They represent sophisticated signaling platforms that regulate ROS production, metabolite flux, and cellular stress responses. The spatial organization of respiratory complexes influences how electrons flow through the chain, affecting both energy production and generation of signaling molecules, such as superoxide and hydrogen peroxide. Furthermore, my work on aging mechanisms connects directly to mitochondrial retrograde signaling pathways that communicate cellular stress to the nucleus, triggering adaptive responses or, when dysregulated, contributing to age-related pathologies.

MitoWorld: It seems that “signaling” always must be added to any mitochondrial discussion to get beyond the APT/powerhouse conversations. Talk about how we should see mitochondria and mtDNA as part of the signaling functions in cells with the nucleus and beyond.

Enríquez: The persistent need to add “signaling” to mitochondrial discussions reflects decades of reductionist thinking that portrayed mitochondria solely as cellular powerhouses. This ATP-centric view, while historically important, has become a conceptual limitation that obscures the true complexity of mitochondrial function. Mitochondria and mtDNA function as integrated signaling networks with multiple mechanisms.

• Metabolite signaling: Mitochondria produce signaling metabolites (e.g., α-ketoglutarate, succinate, acetyl-CoA, and citrate) that directly regulate nuclear gene expression through epigenetic modifications. These metabolites serve as cofactors for chromatin-modifying enzymes, linking mitochondrial metabolism to nuclear transcriptional programs.
• ROS as signal transducers: Rather than just being toxic byproducts, mitochondrial ROS function as essential signaling molecules that activate stress-responsive pathways, regulate hypoxia responses, and control cellular fate decisions. The spatial and temporal regulation of ROS production allows mitochondria to communicate specific information about cellular energetic and redox status.
• Retrograde signaling pathways: Mitochondria communicate their functional status to the nucleus through calcium-calcineurin signaling, AMPK activation, and transcription factor regulation. These pathways allow cellular adaptation to mitochondrial dysfunction and coordinate nuclear gene expression with mitochondrial needs.
• mtDNA as an inflammatory signal: Cytoplasmic release of mitochondrial DNA activates innate immune pathways through cGAS-STING signaling, linking mitochondrial damage to inflammatory responses. This represents a fundamental immune surveillance mechanism that monitors mitochondrial integrity.

MitoWorld: List and discuss the various types of signaling and the ones you personally are interested in.

Enríquez: The diversity of mitochondrial signaling mechanisms reflects the evolutionary origin and cellular integration of these organelles.

• Metabolite-mediated signaling: This includes one-carbon metabolism products (SAM, formate), TCA cycle intermediates (α-KG, succinate, fumarate), and lipid signaling molecules (cardiolipin, ceramide). These metabolites regulate epigenetic modifications, transcriptional programs, and enzymatic activities throughout the cell.
• ROS Signaling: Different mitochondrial sites produce distinct ROS species with specific signaling functions. Complexes I and III generate superoxide with different submitochondrial localizations, affecting cytoplasmic versus matrix signaling pathways. H₂O₂ serves as a diffusible signaling molecule that modifies cysteine residues on target proteins.
• Calcium signaling: Mitochondria function as calcium buffers and signal processors, with calcium uptake and release coordinating with cellular calcium oscillations to regulate gene expression, enzyme activities, and cellular excitability.
• Mitokine secretion: Mitochondrial stress triggers the release of signaling proteins, such as FGF21, GDF15, MOTS-c, and Humanin, that act in autocrine, paracrine, and endocrine manners to coordinate tissue responses. These represent a new class of stress-responsive hormones.
• Intercellular mitochondria or mitochondrial components transfer: Direct transfer of mitochondria or mitochondrial components between cells represents a mechanism for intercellular signaling that can modify recipient cell function.
• Epigenetic regulation: Mitochondrial function directly influences nuclear chromatin structure through metabolite availability, NAD+/NADH ratios, and histone modification enzyme activities. This creates a direct link between mitochondrial metabolism and gene expression programs.

Personally, I am most interested in ROS signaling mechanisms and metabolite-mediated epigenetic regulation, as these directly relate to my research on respiratory complex assembly and aging mechanisms.

MitoWorld: If we are to re-define mitochondria how important is signaling and what might the inclusive definition include?

Enríquez: Signaling is critically important because it represents the mechanism by which mitochondria integrate their traditional functions with cellular and organismal physiology. Without signaling, mitochondria would be isolated organelles incapable of coordinating their activities with cellular needs or communicating their status to other cellular compartments. The new paradigm recognizes mitochondria as “cellular command centers” that process information, make decisions, and coordinate responses rather than simply executing metabolic programs

MitoWorld: For newcomers to the field, what would you tell them in terms of the importance of signaling in general and mitochondrial signaling in particular?

Enríquez: For students and PhD candidates entering the field, I would emphasize several key points.

• Understanding signaling as fundamental biology: Every cellular process, from development to disease, involves signaling networks. Students should approach mitochondria as integrated systems rather than isolated organelles.
• Interdisciplinary perspective is essential: Modern mitochondrial research requires integration of biochemistry, cell biology, physiology, bioinformatics, and clinical medicine. Students should develop broad competencies and collaborative skills to address complex mitochondrial questions.
• Technical diversity: The field requires expertise in diverse methodologies—from single-cell analyses and live imaging to omics approaches and animal models. Students should gain experience with multiple technical approaches to study mitochondrial function.
• Clinical relevance: Mitochondrial signaling dysfunction underlies numerous diseases, including cancer, neurodegeneration, metabolic disorders, and aging. Understanding the translational potential of basic research enhances both scientific impact and career opportunities.

Students must understand that signaling represents the mechanism by which mitochondria exert their biological effects beyond energy production. Dysregulated signaling, not simply energy deficiency, underlies most mitochondrial contributions to disease pathology.

We invite you to read our new article, “Welcome to the Mitoverse,” featured in the October 2025 issue of STEM Magazine—a widely read online publication reaching K–12 STEM teachers, college instructors, and faculty across the United States and beyond.

We’re thrilled to bring the world of mitochondria to a broader educational audience as part of www.MitoWorld.org’s mission to expand understanding of cellular dynamics, the mitochondrial genome, and the crucial mito-nuclear axis.

Why We Wrote “Welcome to the Mitoverse”

As we developed the article—written as an FAQ on MitoWorld—we realized how few straightforward, accurate, and well-referenced explanations exist for what mitochondria really are: their origins, their roles in health and disease, and their central place in modern biology and medicine.

We also recognized a deeper challenge. While genetics and the microbiome have each had their revolutions, the mitochondrial revolution is only beginning. Raising awareness must start early—in schools—where students’ natural curiosity can be fostered with accurate, up-to-date narratives about how life works.

Help Us Build a Mito-STEM Curriculum

This publication represents an opportunity to start a new effort we call MITO-STEM— partnerships connecting K–12 teachers, college instructors, and mitochondrial researchers. Our hope is to engage educators who want to introduce students to the remarkable world of mitochondria: their dynamic structure, their unique DNA, and their continuous dialogue with the nucleus and the rest of the cell.

In most biology classrooms, cells are still depicted as static spheres with a few scattered mitochondria—an image that bears little resemblance to reality. Yet understanding how mitochondria actually function, and how they dynamically coordinate and communicate with the nucleus, is essential to understanding life itself.

If you are interested in participating, please contact info@mitoworld.org

Mainstreaming Mitochondria

At MitoWorld, our mission is to mainstream mitochondria—to make their importance visible in both public understanding and medical research. Greater awareness will help drive funding for conditions ranging from rare mitochondrial diseases at birth to neurodegenerative disorders in later life.

By connecting scientists and educators through MITO-STEM, we hope to reshape how biology is taught and understood—inspiring students to see the living cell as a vibrant, interconnected system and mitochondria as its central players.

We invite teachers, researchers, and institutions to join us in this effort. Read “Welcome to the Mitoverse” in STEM Magazine’s October 2025 issue, and explore how you can get involved at www.MitoWorld.org.

Stealth BioTherapeutics, Inc, (Stealth) has received FDA approval for its drug FORZINITY™ (Elamipretide Injection). The drug is used to improve muscle strength in adult and pediatric patients over 30 kg with Barth syndrome, a rare and life-limiting disease. FORZINITY is the very first mitochondrial-targeting therapy approval.

“FDA approval culminates more than a decade of clinical development,” said Reenie McCarthy, Stealth CEO. “We were inspired by patient advocacy to start our development journey and patients remained our north star along the way, strengthening our resolve through every challenge.”

Barth syndrome is a life-limiting pediatric disease that affects only about 150 people in the United States. The disease is caused by a mutation in the TAFAZZIN (TAZ) gene that results in the loss of tetralinoleoyl-cardiolipin, a key lipid for mitochondria. It is an x-linked disease, which means that females can be carriers, but typically only males are affected. Patients suffer from exercise intolerance, muscle weakness, debilitating fatigue, heart failure, recurrent infections, and delayed growth. The greatest risk of death occurs before age 5.

Mitochondria are tiny cell organelles primarily known for producing energy within the cell, but they also have many other important activities. Each cell contains hundreds to thousands of mitochondria. Mitochondria are also unique in that they contain their own DNA. They are increasingly implicated in many diseases, but, to date, there have been no successful drug interventions of the mitochondria themselves.

“We are grateful for and applaud this incredible step that was reached expeditiously by the FDA after Stealth’s most recent new drug application and after years of circuitous challenges,” said Emily Milligan, MPH, executive director of Barth Syndrome Foundation (BSF). “We have worked tirelessly to support this outcome, and today is a day to celebrate, although much work remains.”

Elamipretide is reported to show improvement in mitochondrial structure and function in a cardiolipin-dependent manner, resulting in improved heart and skeletal muscle function ^2-5. It readily enters mitochondria and migrates to the mitochondrial inner membrane ²,⁶. Once there, it specifically binds to cardiolipin to improve membrane stability, enhance ATP synthesis, and reduce the production of reactive oxygen species.

Simona Lobasso, PhD, an expert on lipidomics and cardiolipin role at the University of Bari, Italy, recently reported ⁴ that Elamipretide treatment improves ultrastructural morphology (i.e., inner membrane and cristae) and function in isolated cardiac mitochondria by restoring their ability to recycle themselves within the heart cells in a mouse model of Barth syndrome.

She added, “In a previous study,⁴ we found that in vivo treatment of TAZ-deficient mice with Elamipretide promoted respiratory “supercomplex” organization in cardiac mitochondria. We hypothesize that it exerts its beneficial effect by entering mitochondria and influencing the function of the respiratory chain. By improving mitochondrial structure, respiratory capacity and dynamics, Elamipretide can also improve overall heart and skeletal muscle functions in treated mice.”

Michael Murphy, PhD, a noted mitochondrial expert at the University of Cambridge who is not associated with Elamipretide or its approval process, but familiar with clinical trials and FDA drug approval offered, “The approval of Elamipretide for Barth syndrome patients arose from an open label 168-week trial of 10 patients with eight completing the trial with functional improvements being reported.” He added, “This is a potentially good step for this group of patients who have few treatment options. While this outcome cannot be compared with a long-term placebo-controlled double-blind study, the small number of patients and their prognosis make this challenging.”

Such breakthroughs are critical for the support foundations. “BSF will continue its efforts to advocate for label expansion to include individuals under 66 pounds and monitor Stealth’s progress on meeting post-approval requirements and coordinating with our international affiliates to expand access internationally.” said Lindsay Marjoram, PhD, BSF director of research.

“While we are thrilled to have achieved this milestone, we are keenly aware that our work is not done,” said Jim Carr, Stealth chief clinical development officer. “We took the weekend after the approval to celebrate and then leaned right back in to initiate activities for our post-marketing trial, which will enroll 48 subjects, age 5 and older, at sites in Europe and Australia. We also plan to meet with the FDA in the next few months to align on a pathway toward expanding the label to include younger children.”

Stealth plans to continue working on elamipretide for additional indications, including children less than 30 kg with Barth syndrome and dry age-related macular degeneration and primary mitochondrial myopathy. In addition, they are developing bevemipretide for ophthalmic and neurological disease indications.

Questions for about the approval process and the prospects for the disease:

MitoWorld: FDA approval of elamipretide is a landmark achievement. Do you think this will encourage other pharm and biotech companies to pursue therapies for these rare diseases?

Lindsay T. Marjoram (LTM): It is our hope that this approval will help kickstart future investments into both mitochondrial and ultra-rare diseases. I think this approval helps to demonstrate that the FDA is more committed to using the accelerated approval pathway in ultra-rare drug submissions. To spur future investment, though, it will be critical for Congress to reauthorize the Pediatric Priority Review Voucher Program, which gives companies, such as Stealth, the financial incentive to invest in diseases that may not be profitable.

MitoWorld: Can you elaborate on the molecular mechanism of elamipretide?

LTM: Elamipretide is a mitochondrial cardiolipin binder that localizes to the inner mitochondrial membrane and improves mitochondrial morphology and function. In Barth syndrome, lack of TAFAZZIN activity leads to a build-up of immature (monolyso-) cardiolipin and alters the structure of the inner membrane. The impaired structure leads to decreased energy production.

MitoWorld: Barth syndrome is a rare disease. How hard was it to identify study a sufficient number of subjects to obtain significant results?

LTM: BSF was a partner in ensuring that the trial was enrolled. I believe it took less than a year to fully enroll. There were a lot of learnings from this process since it was the very first trial to be run in our community. One thing we learned from this trial was that it needed to run longer than anticipated.

MitoWorld: Are you looking at other drug candidates for mitochondrial diseases?

David Brown, PhD, Stealth senior vice president of discovery: Our next generation clinical stage compound, bevemipretide, is in early clinical trials, and we have a deep pipeline of mitochondrial targeted therapeutics in early stage development.

LTM: BSF has funded >$7M in research, which has resulted in >$41M in follow-on funding from agencies, such as NIH. The Foundation continues to support research into the basic mechanistic underpinnings of Barth syndrome and development of potential therapeutics, including enzyme replacement therapy, AAV-mediated gene therapy, anti-sense oligonucleotide therapy, and small-molecule development.

References

¹ U.S. Prescribing Information:

https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/215244s000lbl.pdf

² Szeto HH (2014) First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br. J. Pharmacol. 171: 2029–2050.

³ Chatfield KC, et al. (2019) Elamipretide improves mitochondrial function in the failing human heart. JACC: Basic Transl. Sci. 4: 147–157.

⁴ Russo S, De Rasmo D, Rossi R, Signorile A, Lobasso S (2024) SS-31 treatment ameliorates cardiac mitochondrial morphology and defective mitophagy in a murine model of Barth syndrome. Sci. Rep. 14: 13655.

⁵ Russo S, De Rasmo D, Signorile A, Corcelli A, Lobasso S (2022) Beneficial effects of SS-31 peptide on cardiac mitochondrial dysfunction in Tafazzin knockdown mice. Sci Rep. 12: 19847.

⁶ Sabbah HN, Alder NN, Sparagna GC, Bruce JE, Stauffer BL, Chao LH, Pitceathly RDS, Maack C, Marcinek DJ (2025) Contemporary insights into elamipretide’s mitochondrial mechanism of action and therapeutic effects. Biomedicine & Pharmacotherapy 187: 118056.

Mitochondria Fight Pathogens by Starving Cells of Folate

In a recent paper in Science, a research team led by Lena Pernas of UCLA showed that cells infected with a pathogen activate their mitochondria to gobble up the available folate.

Mitochondria are deeply involved in cellular metabolism and use many of the nutrients that a pathogen need. Is this competition for resources simply a coincidence, or is it a strategy to protect against pathogens? The Pernas group focused on the replication of mitochondrial DNA (mtDNA), which requires the materials for nucleotide biosynthesis. For a model pathogen, they used the protozoan parasite Toxoplasma gondii. For the parasite, folate is essential to make thymidine for DNA synthesis and proliferation.

Interestingly, the researchers found that the parasite caused the cells to begin making new mtDNA, which depended on the integrated stress response and its key effector, the activating transcription factor 4 (ATF4). They found that ATF4 turns on one-carbon metabolism, which requires folate, to increase mtDNA. They also noted that disrupting mitochondrial one-carbon metabolism resulted in increased parasite replication.

T. gondii needs folate to make thymidine and new DNA, but ATF4 activation short-circuits that synthetic pathway by depriving the pathogen of folate. They concluded that the cells actually use mitochondrial metabolism as a weapon against pathogens.

A Conversation with Dr. Pernas

MitoWorld: This is an interesting paper about how cells use mitochondria indirectly to defend against a pathogen. Can this phenomenon be generalized to other pathogens or other nutrients?

LP: I think so—especially for pathogens that depend on host nutrient that can be sequestered or consumed by host mitochondria.

MitoWorld: What might be the next steps in your research into this action?

LP: Our immediate next steps are to understand if we can pharmacologically enhance mito1C during infection to restrict parasite growth, and to define other ways mitochondria limit pathogen replication.

MitoWorld: Are there any harmful side-effects of using up a portion of the folate in the cell? LP: This is such an exciting question! Another way to think of it is: can mitochondria become ‘selfish,’ and limit critical nutrients for the cell? That’s a concept that Dr. Tania Medeiros (the first author) will explore in her lab. I don’t think transient activation of mito-1C has harmful side-effects. However, in cases of mitochondrial disease where mito-1C enzymes are chronically activated, this may harm the host cell by restricting folate needed for other processes—analogous to the limiting of dTTP by dysfunctional mitochondria from nuclear genome replication, as Anu Suomalainen-Wartiovaara (U. of Helsinki) has shown.

MitoWorld: Is the mtDNA made in response to the pathogen simply degraded?

LP: We don’t have any evidence for degradation. One puzzling result is that, although mtDNA levels increase, we don’t see a corresponding increase in mtRNA or mtDNA-encoded proteins. One possibility is that the parasite produces an effector that inhibits the translation of mtDNA-encoded proteins.

MitoWorld: Can you speculate on whether this phenomenon might be used therapeutically? LP: It might be difficult since folate is a critical vitamin for multiple processes. I can speculate that increasing folate concentrations may not be beneficial during infection. In fact, elevated serum folate has been associated with increased malaria parasitemia in humans. Plasmodium, the causative agent of malaria, is another parasite that relies on folate for dTMP synthesis. Rather, we should consider how to specifically enhance mito1C, or mitochondrial use of folate. Another point is that the inhibition of the ISR has been explored in different disease contexts, but if this blocks mito1C, it may be important to first test individuals for pathogen burden.

MitoWorld: How did you become interested in mitochondria in the first place?

LP: When I started graduate school, my PhD advisor (John Boothroyd, Stanford U) showed me an electron micrograph of a monocyte isolated from a mouse infected with Toxoplasma. I couldn’t stop thinking about why all the mitochondria of that cell were surrounding the parasite. I’ve been working on this question ever since!

Reference

Medeiros TC, Ovciarikova J, Li X, Krueger P, Bartsch T, Reato S, Crow JC, Tellez Sutterlin M, Martins Garcia B, Rais I, Allmeroth K, Hartman MD, Denzel Ms, Purrio M, Mesaros A, Leung K-Y, Greene NE, Sheiner L, Giavalisco P, Pernas L (2025) Mitochondria protect against an intracellular pathogen by restricting access to folate. Science 389(6761): eadr6326.

In a paper published in Nature Metabolism, a multi-institute research team, led by Timothy A. Ryan of Weill Cornell Medicine, found that the balance of lipid droplet (LD) metabolism and catabolism is critical to the transmission of nerve impulses at the synapse.

For some time, the brain has been assumed to use glucose almost exclusively as an energy source. Triglycerides were not considered to have a role in energy production as the stored form of these fat molecules, LDs, are rarely seen in healthy neurons. The discovery of a neuron-specific TG lipase, DDHD2, caused a closer look at TG metabolism in the brain. Loss of DDHD2 activity results in a buildup of LDs in neurons and cognitive impairments in a variant of a condition called hereditary spastic paraplegias in humans.

They found that blocking DDHD2 or of the mitochondrial lipid transporter CPT1 led to torpor in mice. Furthermore, they found that blocking DDHD2 in dissociated neurons causes LDs to accumulate in neurons, particularly at nerve terminals.

They suggest a complex model in which LDs at the synapse are in a careful balance. They found that fatty acids could provide sufficient energy for synaptic vesicle recycling, even in the absence of glucose. They also note the Randal cycle, in which the use of fatty acids and glucose for energy in energy-requiring tissues are tightly regulated and speculate that a similar system might exist in brain. They speculate that fatty acids to fuel neurons may be  transported from non-neuronal cells in the brain by lipoproteins that contain apolipoprotein E, which is known to be associated with Alzheimer’s disease and sent to mitochondria to be used in ATP production. These findings add additional evidence for the involvement of DDHD2 mutations in various diseases.

A Conversation with Dr. Ryan

MitoWorld: You suggest in the Discussion that this process might be more important in aged individuals. Do you have any data on that or plans to follow up on that?

There are several published studies providing evidence that in humans, LDs accumulate in the diseased, aged brain. At present though, getting more mechanistic detail of what is going on is difficult, as the aging process is not easy to model in simpler organisms with complex nervous systems.

MitoWorld: Excess fatty acids are consigned to use to produce energy in the mitochondria. Is that the primary use of those fatty acids, or are they used in membrane repair in the synapse and the leftovers go to the mitochondria?

This remains an open and very interesting question. The brain is mostly made of lipid. Neurons have both very elaborate architectures that extend huge distances, all requiring a plasma membrane made of lipids. Additionally, within neurons another organelle, the endoplasmic reticulum, also extents over the entire extent of the cell. This too is made of lipid. An open and underexplored are is where these lipids are synthesized. Are they all imported and if some from where?  If not where is the biosynthetic machinery to make fatty acids located. Many non-neuronal cells also have elaborate fatty acid demands for their architecture (e.g. Schwann cells). 

MitoWorld: Can you speculate how these results might be used in a therapeutic strategy?

The existence of DDHD2 suggests in neurons and the dramatic impact of perturbing it acutely or chronically (as in HSP54) all point to the likelihood that b-oxidation in neurons is always happening and, therefore, always participating in making ATP to fuel neuron function. Our brains are also famously intolerant of interrupting the fuel supply, as if your plasma glucose drops by a mere factor of 2, most people begin to manifest neurological symptoms. There has been exciting progress in developing potential therapeutic strategies to boost glycolysis. Understanding that this might be supplementing a background level of b-oxdation might clarify the potential variability of boosting glycolysis in different people.

MitoWorld: Other recent papers have commented on the junctions of mitochondria and the endoplasmic reticulum for transfer of materials. Might something like that be involved in the transfer of fatty acids to the mitochondria?

There has been exciting progress in identifying proteins that are responsible for exchanging fatty acids between the endoplasmic reticulum and various organelles. For example, VPS13 is an excellent example of a class of proteins that do this, and mutations in one of the four variants in humans each lead to a different disease. VPS13A is currently considered to be at the interface of the ER, mitochondria and LDs and is therefore a candidate to facilitate the transfer of fatty acids between these organelles.

MitoWorld: This fascinating finding injects fatty acid metabolism into the energy environment of neurons. Do you have any idea of the relative amounts of energy from fatty acids vs glucose?

Classic biochemistry predicts that for every two carbons of a fatty acid you generate one molecule of acetyl-coA in the mitochondria. For each acetyl-coA, you would produce ~ 30-36 ATP molecules.  Glycolysis of a single glucose molecule produces only one acetyl-coA molecule (as well as two net ATP even without mitochondria). So on a per molecule basis fatty acids provide a lot more ATP.

Reference

Kumar M, Wu Y, Knapp J, Pontius CL, Park D, Witte RE, McAllister R, Gupta K, Rajagopalan KN, De Camilli P, Ryan TA (2025) Triglycerides are an important fuel reserve for synapse function in the brain. Nature Metabolism 7: 1392–1403.

In a recent paper in Nature Communications, a research team led by Daria Mochly-Rosen of Stanford University discovered a small protein that facilitates the interactions of other proteins to maintain mitochondrial integrity and function during oxidative stress.

Mitochondria are unusual cell organelles. They have their own DNA and are involved in multiple key activities. Disruption of these activities contributes to many acute and chronic diseases. Mitochondria also have mechanisms, such as fission and fusion, to ensure they maintain their effectiveness. Fusion allows damaged mitochondria to be improved by adding functional components, and fission provides a way to either increase mitochondrial number and/or to eliminate those damaged beyond repair.

Mitochondrial fission is overactivated in times of oxidative stress. The mechanism was partially understood. During stress, this process begins when a protein in the outer mitochondrial membrane called fission protein 1 (Fis1) recruits a GTPase called Drp1 to the outer mitochondrial membrane. In yeast, this interaction is enough to initiate fission in both physiological and stress conditions, but not in humans.

Suman Pokhrel in the Mochly-Rosen lab sought to determine what was missing by using protein studies and genetically engineered cells. Her team discovered that a key cysteine amino acid in Fis1 (Cys41) was critical for the process. Cysteines are often important components of intermolecular associations because they can form disulfide bonds. During oxidative stress, this is just what happens. The two molecules of Fis1 bound together serve to induce excessive fission. Through further research, the team discovered a new drug called SP11 that selectively inhibits dimerization of Fis1 and thus inhibits excessive fission during stress.

The findings of the group, including the discovery of the pivotal role of Cys41 in dimerization, show how mitochondrial fragmentation can be selectively inhibited during oxidative stress. Furthermore, SP11 or other compounds that work like it might become a therapeutic for the treatment of many chronic diseases associated with mitochondrial fragmentation and dysfunction.

A discussion with Dr. Mochly-Rosen

MitoWorld: This is an interesting paper. Can you suggest what might be the next steps in this research?

Mochly-Rosen: We will continue the basic research to examine how Fis1 binds Drp1 and recruits it to the outer mitochondrial membrane. We also plan to continue developing therapeutics that inhibit Fis1 activation during stress. We will keep optimizing these molecules and evaluate their safety and effectiveness in animal models as part of our interest in translating our research to the clinic.

MitoWorld: Your results indicate that there is an extra step in humans compared to yeast. Do you have any speculation on why that extra step would have evolved?

Mochly-Rosen: Humans are multicellular, and their biology is far more complex than a single‑celled organism, such as yeast. As a result, multicellular creatures often evolve new machinery and more finely tuned regulatory mechanisms to carry out complex functions, and the divergence of Fis1 function is one example of that. One interesting observation is that genetically removing Fis1 causes death of mice during embryonic development, implying that Fis1 plays a critical role at embryonic stage. This suggests that in humans, Fis1 evolved to carry out an important role in embryonic development that yeast simply doesn’t need.

MitoWorld: The involvement of Cys41 is an “extra” step in human and other mammalians. However, that still begs the question of what signal initiates fusion. Do you know what the beginning step is yet?

Mochly-Rosen: Cys residues are sensitive to oxidative stress and their SH moiety in two Cys residues that are close enough to each other losses the proton (H) to generate an S-S bond between these adjacent residues, thus linking the two Fis1. The dimeric Fis 1 can now bind dimeric Drp1 to trigger mitochondrial fission. Thus, oxidative stress is required to activate this process, and by inhibiting the dimerization, the mitochondria are protected.

MitoWorld: This paper goes a long way to explain the mechanism for pathological fission. Is it too simple to hope that some aspects of this work would be helpful in unraveling the fusion process?

Mochly-Rosen: Mitochondrial fusion and fission are driven by distinct protein machinery within cells. Although mechanistic understanding of fission components alone doesn’t directly provide insights into understanding the fusion process, it helps reveal how these processes are balanced and suggests that dimerization of the components is the first step in their activation. Our research will examine this possibility.

MitoWorld: You have already done considerable work on possible therapeutic agents. Might it be a drug that uses the phenothiazine moiety and mimics SP11’s actions? Do you plan to follow up on your work in mice?

Mochly-Rosen: Our molecule, SP11, needs further development to improve its drug properties. We need to be sure the molecule is completely safe and sufficiently stable so it stays in the body long enough to exert its effect. Once we’ve optimized for safety and stability, we plan to test this new series of molecules in animal disease models.

MitoWorld: What caused you to become interested in mitochondria in the first place?

Mochly-Rosen: Way back, almost two decades ago, we looked at cells from rats with high blood pressure and noticed their mitochondria were a lot more broken up than usual. When we treated animals with neurodegenerative diseases with compounds that prevented that fragmentation, they got better. Since then, we’ve been interested in understanding this pathological mitochondrial fission and discovering chemical agents that block fragmentation. The more I’ve learned about mitochondria, the more fascinated I’ve become with these organelles. Today I believe that having healthy mitochondria is the key to healthy cells and thus to healthy organs and a healthy body. New medical interventions that target mitochondria won’t necessarily cure all diseases, but by reducing the burden on the cell, they can allow it to heal itself—and even other cells. I’ve been following the remarkable progress in mitochondrial research over the past few years, and I’m hopeful that discoveries in the field will translate into solutions that help patients.

Reference

Pokhrel S, Heo G, Mathews I, Yokoi S, Matsui T, Mitsutake A, Wakatsuki S, Mochly-Rosen D

(2025) A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress. Nat Commun 16: 4187.

https://doi.org/10.1038/s41467-025-59434-6

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In a paper¹ published in Nature Metabolism, a research group at the University of Helsinki led by Pekka Katajisto, examined the effect of organelle age on cell fate determinations in tissues. Interestingly, they found that asymmetric cell divisions concentrate older mitochondria in stem cells that are more efficient in tissue renewal.

Specifically, the team sought to test the hypothesis that metabolism is a major factor in cell fate decisions and regeneration. They studied mouse intestinal stem cells (ISCs) that inhabit the crypts in the intestine where new intestinal epithelial cells are created to replace those normally worn out. They developed methods to isolate ISCs, based on the age of their mitochondria.

They were particularly interested in a subset of ISCs enriched with older mitochondria. While many other characteristics of this subset were similar to other ISCs, they did have some intriguing aspects. They form organoids more readily, which is consistent with their ability to reform their niche cells, thus leading to better resistance to damage by chemotherapy. They produce more a-ketoglutarate (aKG) that has many activities, including the ability to change epigenetics.

In summary, they found that in ISCs the aged mitochondria regulate cell fate. The findings suggest future treatment strategies that target the found metabolic mechanisms.

A Discussion with Dr. Katajisto

MitoWorld: What do you see as the next steps in your work? For example, you suggest that epigenetic changes (e.g., with aKG) might drive this process. Do you plan to look at that possibility?

Yes, we do already know that the process is dependent on epigenetic modifiers of the TET group of enzymes that hydroxymethylates methylated cytosines in the DNA. Interestingly, out of the relatively small set of genes with changes in this mark in ISC with old mitochondria, surprisingly many have been linked to processes related to regeneration or niche cell differentiation. We are currently probing if hydroxymethylation of these genes is crucial for the first steps of fate determination as ISCs become niche cells.

MitoWorld: Your paper suggests some fascinating possibilities. Can you speculate on the mechanism that allows the older mitochondria to be segregated during cell division? Is the relative success of cells with older mitochondria determined purely by energy needs?

The answer is that we don’t know yet. Somehow the cell must be able to recognize domains of the mitochondrial network based on their age as they enter mitosis. In our previous work² using human asymmetrically dividing cell lines, we saw that older mitochondria localize closer to the nucleus. But how they are recognized and asymmetrically segregated in the cell we don’t yet know. We don’t think the intestinal stem cells with older mitochondria necessarily produce more energy in the form of ATP, as their morphology is not consistent with having higher oxidative phosphorylation capacity. However, again in our previous work³ we did see that older mitochondria in cultured cells have higher oxphos capacity. In the ISCs it seems to be instead the relative amount of the TCA intermediates aKG, succinate  and 2-HG, which are crucial for the success of ISCs with old mitochondria in generating niche cells faster, and subsequently regenerate the epithelium.

MitoWorld: It has been hypothesized that aging began from the asymmetric division in bacteria. It is interesting that mitochondria, which derived from bacteria, have continued this practice in other settings. Is this as common a phenomenon as it might seem?

Katajisto: What a fascinating question. Although we have not looked into this it is quite possible that some of the mechanisms allowing of segregation of mitochondria of different age could be common to their bacterial ancestors, as are many other features of mitochondria. In any case, the discovery of seemingly separate sub-pools of mitochondria that are also selectively and asymmetrically segregated in cell divisions, raises interesting questions also for example on regulation of fission and fusion dynamics of mitochondria.

MitoWorld: The reprogramming of cells to iPSCs and other cell types has become routine in labs and showed the plasticity of cell fate commitments. Any thoughts on how mitochondrial aging and segregation fares in those protocols?

Katajisto: It is indeed interesting to look into this phenomenon in many iPSC-derived differentiations as introduction of our construct is relatively straightforward. However, the high amount of growth factors and inhibitors used in the in vitro differentiation protocols to force specification of certain lineages and cell fate may override naturally occurring subtle mechanisms, such as the metabolism imposed by age-selective mitochondrial segregation. We are currently looking for example into how mitochondrial age impacts the functional maturity of PSC derived pancreatic beta cells.

MitoWorld: This is an important finding for science. Can you see any treatment possibilities down the road? For example, might aKG supplementation be helpful? Or on a more speculative note, if the cell-to-cell transfer of mitochondria can be mastered, might those transfers be beneficial?

Katajisto: In our work, we found that giving aKG to old mice for 2 weeks before administration of the commonly used chemotherapeutic drug 5-FU promoted their recovery after the treatment known to cause severe side effects particularly in elderly patients. Thus, we think that aKG administration indeed has potential in chemoprotection, but we of course have to first test how aKG impacts the effectiveness of the drug against cancer. Mitochondrial transfer is another fascinating avenue, and it might well be that the differentiation potential or fitness of cells that are to be used for cellular therapy could be boosted with the transfer of the right kind of mitochondria. However, the effect from transferred mitochondria would probably be very transient, and so strategies targeting or mimicking the age-specific traits of mitochondrial metabolism by other means are likely going to be more practical.

Katajisto: MitoWorld: What drew you to the study mitochondria in the first place?

Originally,² I set out to study if age-dependent segregation of organelles is a feature of mammalian asymmetrically dividing cells with the thought that stem cells might push the older, possibly damaged organelles, into the differentiating daughter cell to keep the stem cell pool healthy. Mitochondria³ and peroxisomes⁴ were found to be asymmetrically segregated between the differentiating and self-renewing daughter cells, but it turned out that old organelles were not damaged, just metabolically different. Thus, I started studying mitochondria because they were the most striking age-dependently segregated organelle in my original findings, using the human cell line, and it turned out that this was also taking place in tissue resident stem cells in mice.

References

¹Andersson S, Bui H, Viitanen A, Borshagovski D, Salminen E, Kilpinen S, Gebhart A, Kuuluvainen E, Gopalakrishnan S, Peltokangas N, James M, Achim K, Jokitalo E, Auvinen P, Hietakangas V, Katajisto P (2025) Old mitochondria regulate niche renewal via α-ketoglutarate metabolism in stem cells. Nat Metab 7:  1344–1357.

²Katajisto P, Döhla J, Chaffer CL, Pentinmikko N, Marjanovic N, Iqbal S, Zoncu R, Chen W, Weinberg RA, Sabatini DM (2015) Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness. Science 348: 340–343.

³Döhla, J., Kuuluvainen, E., Gebert, N. et al. (2022) Metabolic determination of cell fate through selective inheritance of mitochondria. Nat Cell Biol 24: 148–154.

⁴Bui, H., Andersson, S., Sola-Carvajal, A. et al. (2025) Glucose-6-phosphate-dehydrogenase on old peroxisomes maintains self-renewal of epithelial stem cells after asymmetric cell division. Nat Commun 16: 3932.