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.
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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.
A paper1 recently published in Science explored the fascinating question of how the mitochondrial genome affects cellular function. The research work was carried out at the University Medical Center of Gottingen, led by Prof. Peter Rehling and Luis Daniel Cruz-Zaragoza (currently Professor at the Department of Biology, Université de Sherbrooke). Through a multi-institutional collaboration, the team developed a method to silence the translation of specific mitochondrial mRNAs selectively and used it to gain a deeper understanding of how mitochondria regulate translation.
Human mitochondria have their own small circular genome that encodes genes for essential proteins needed for oxidative phosphorylation. However, they are also involved in many other cellular functions, and most of the genes for those other functions are contained in the nuclear genome. The interactions of the two genomes are one of the most interesting open questions in biology today. Dissecting the translation of mitochondrial mRNAs has been challenging because standard methods (e.g., CRISPR) do not work inside mitochondria.
To overcome this challenge, the scientific team used synthetic peptide-morpholino chimeras to inhibit translation of specific mitochondrial genes. These synthetic molecules combine the phosphorodiamidate morpholino oligonucleotides directed against a specific mRNA with a mitochondrial targeting signal (or presequence). The chimeric molecules entered the mitochondria and blocked translation. By inhibiting the synthesis of each protein under different conditions, the researchers could ascertain the particular cellular response upon depletion.
With this study, the team identified proteins involved in the biogenesis and activity of the oxidative phosphorylation complexes. They also gained insights into how the cell deals with the loss of a key protein. Ultimately, the method can be applied to numerous other studies in mitochondrial biology.
Conversation with Dr. Cruz-Zaragoza
MitoWorld: Polymorpholino oligonucleotides are typically used as antisense oligonucleotides. Why did you decide to apply them for targeting the expression of mitochondrially encoded genes?
LDCZ: Close to 99% of proteins in the human mitochondria are encoded in the nuclear genome, translated in the cytosol, and imported into the mitochondria. Several genetic approaches are available to study and understand the function of this group of proteins, including CRISPR-Cas9, siRNA, epigenomic expression, and genomic integration. Those methods require the use of nucleic acids. Although transfecting nucleic acids into a cell is relatively straightforward, the same doesn’t apply to the mitochondria.
Mitochondria have two membranes: the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM). The electron transport chain (ETC) is localized on the IMM. The activity of ETC generates a potential difference across the mitochondrial membrane, known as the mitochondrial membrane potential, making the IMM’s luminal side negatively charged. Therefore, it is no surprise that the introduction of nucleic acids into the mitochondria is highly inefficient, hindering efforts to apply genetic engineering to mitochondrial gene expression. Remarkably, researchers have developed several solutions based on proteins, such as base editors and mito-zinc finger protein nucleases.
We expected that non-charged oligonucleotides, such as phosphorodiamidate morpholino oligonucleotides, should be better imported into mitochondria. To target the morpholinos (MO) to the mitochondria, we initially fused the MO to a protein carrier via click chemistry, generating protein-MO chimeras. We applied this initial approach in isolated mitochondria.2
However, it did not escape our attention that a more versatile method was required for use in living cells. Therefore, building on our previous work, we optimized the chimera stability and efficiency by replacing the protein component with a mitochondrial targeting signal peptide.1
MitoWorld: What experiments do you have planned to extend this work?
LDCZ: It was thrilling to develop this expression-silencing project. For our recently published work, I had the opportunity to work with several talented graduate students. In addition, the collaborators who participated in our study are remarkable, combining expertise in proteomics (Bettina Warscheid’s group), microscopy (Stefan Jakob’s group), and transcriptomic data analysis (Michael Lidschreiber’s group). So, exciting work is in the making at University Medical Center of Gottingen.
I recently established my lab at the Université de Sherbrooke in Canada. As part of our research program, we will address the functional aspects of mitochondrial RNA life using the peptide-MO chimeras. We will follow an RNA-centered approach and examine how it correlates with the traditional protein-centered one. Luckily, Quebec, and Sherbrooke in particular, has an excellent group of scientists working in RNA biology as part of the RiboClub and the DNA to RNA Initiatives. Exciting times ahead!
MitoWorld: Were you able to link the loss of a specific protein to any human disease?
LDCZ: In our work, we explored the cellular response to challenges associated with the inhibition of subunits encoded in the mitochondrial genome. We have not yet made a direct comparison with mtDNA human disease models. However, it is an attractive problem that we, and other labs, will follow up on. One exciting aspect of our approach is the possibility of revealing and understanding, at the cellular level, the initial stages of defects in mitochondrial gene expression. In the field, researchers traditionally study patient-derived cells that have undergone long-term adaptation. However, silencing mitochondrial transcripts recapitulates the initial chronic depletion of proteins produced in the mitochondria, allowing us to examine how the cell responds and adapts to the challenge. In fact, one can study the onset of the disease in specialized cells, such as cardiomyocytes and hepatocytes. Therefore, this could be extended to other cell types, such as neurons and oocytes. This could contribute to the development of better therapies for mitochondrial diseases.
MitoWorld: Do you see any clinical or diagnostic applications for this methodology?
LDCZ: That is a great question. We can now tune the expression of specific genes encoded in mtDNA. This would allow for controlling the assembly rate of proteins with different genetic origins (nuclear and mtDNA) that form the respiratory complexes, which could be an avenue for treating disorders where the balance is lost. However, some aspects must be addressed before. The most important one is to show that the silencing approach is working in animal models.
MitoWorld: What drew you to mitochondria in the first place?
LDCZ: I have always been intrigued by the eukaryotic cell compartments. During my doctoral studies in Ralf Erdmann’s group at Ruhr-Universität Bochum, I investigated the peroxisome, focusing on its biogenesis mechanisms and function. I enjoyed it very much as part of the Marie Curie Initial Training Network PERFUME (PERoxisome, FUnction, MEtabolism). While attending conferences about protein targeting, I saw how exciting the research in mitochondria was. After finishing my PhD, I joined Prof. Rehling’s group to study mitochondrial protein import. Later, I became interested in working on mitochondrial gene expression. Combining my scientific interests in protein import and gene expression was central to devising the strategy of importing protein-MO chimeras to regulate mitochondrial gene expression.
References
1Cruz-Zaragoza LD, Dahal D, Koschel M, Boshnakovska A, Zheenbekova A, Yilmaz M, Morgenstern M, Dohrke JN, Bender J, Valpadashi A, Henningfeld KA, Oeljeklaus S, Kremer LS, Breuer M, Urbach O, Dennerlein S, Lidschreiber M, Jakobs S, Warscheid B, Rehling P (2025) Silencing mitochondrial gene expression in living cells. Science DOI: 10.1126/science.adr3498.
2Cruz-Zaragoza LD, Dennerlein S, Linden A, Yousefi R, Lavdovskaia E, Aich A, Falk RR, Gomkale R, Schöndorf T, Bohnsack MT, Ricarda Richter-Dennerlein R, Henning Urlaub H, Peter Rehling P (2021) An in vitro system to silence mitochondrial gene expression. Cell 184: 5824–5837.
A recent paper in Science Advances describes the findings of a research team led by Mondira Kundu, MD, PhD, at St. Jude Children’s Research Hospital. The study investigates how mitochondrial (mt) DNA mutations influence leukemia pathology. Unexpectedly, their research showed that a moderate burden of mtDNA mutations can enhance the development of leukemia. They also show that cancer can be re-initiated by inhibiting a specific enzyme in cells carrying a high burden of mtDNA mutations.
Cancers are highly energy dependent, with the mitochondria serving as the cell’s main energy producers. While most research into this connection has focused on mutations in nuclear DNA that affect mitochondrial function, Dr. Kundu’s team explored whether mutations directly in the mtDNA contribute to tumor development.
The researchers began with three lines of mice expressing a mutant exonuclease-inactive mitochondrial DNA polymerase (Polgmut) that lacks accurate proofreading ability. These lines possess either zero (Polgwt/wt), one (Polgwt/mut), or two (Polgmut/mut) copies of the mutated allele, resulting in a graded accumulation of mtDNA mutations. Hematopoietic progenitor cells (HPCs) were isolated from these mice and engineered to express NMyc, a member of the MYC family of transcription factors. Members of the MYC family are commonly dysregulated in many blood cancers, such as leukemia. By transplanting these HPCs into irradiated recipient mice, the team assessed the impact of different levels of mtDNA mutations on cellular metabolism and cancer development.
The findings were unexpected: while metabolism was reduced in mice with either heterozygous or homozygous mutant cells, mice with a moderate mutation load (Polgmut/wt) were more prone to tumor formation than those with a high mutation load (Polgmut/mut). Metabolic plasticity was affected by the number of mtDNA mutations and was critical to the tumorigenic potential of the HPCs. In essence, a moderate number of mutations makes cells more metabolically flexible and more carcinogenic, whereas extensive mutations diminish both their metabolic flexibility and cancerous potential.
Conversation with Dr. Kundu
MitoWorld. Your results are unexpected. Do you have any thoughts on why the partially damaged mitochondria would be beneficial to the cancer? Yes, it appears that partially damaged mitochondria create a unique metabolic environment that cancer cells can exploit. Moderate mitochondrial dysfunction may allow for metabolic reprogramming—enhancing glycolysis and other pathways that support rapid cell growth—without fully compromising energy production. This balance may give cancer cells a survival and growth advantage.
MitoWorld. Can you speculate on how the damaged mitochondria are able to increase their metabolic support for the tumors? Damaged mitochondria may trigger adaptive responses in cancer cells, activating alternative metabolic pathways and stress responses. For instance, partial mitochondrial dysfunction can increase the reliance on glycolysis (the Warburg effect) and other biosynthetic pathways, thereby supporting both energy needs and the synthesis of cellular building blocks required for proliferation. The cells remain metabolically flexible, which is crucial for tumor growth.
MitoWorld. You note both similar and different results with this mutation and different cancers. To what would you attribute those varying results? The impact of mtDNA mutations likely depends on the tissue context and the specific metabolic requirements of different cancers. Some tumors may be more resilient to mitochondrial dysfunction, while others are more dependent on intact mitochondrial metabolism. Additionally, the interplay between mtDNA mutations and nuclear gene mutations can vary, influencing how cells adapt metabolically and whether they become more or less tumorigenic.
MitoWorld. Your results show that inhibiting pyruvate dehydrogenase kinase improved the ability of the homozygous mutant to cause tumors. Does this observation have any therapeutic implications? While our findings are not immediately translatable to therapy, they do highlight the critical role of metabolic plasticity in leukemogenesis. The fact that inhibiting pyruvate dehydrogenase kinase (PDK) restored the proliferative capacity of homozygous mutant HPCs suggests that metabolic pathways can profoundly influence tumor development. This raises the possibility that targeting metabolic enzymes like PDK could one day be leveraged to modulate cancer cell growth, either by restricting the metabolic flexibility of cancer cells or by exploiting specific metabolic vulnerabilities. However, more research is needed, especially since the mutation burden in human leukemias typically comes from single mtDNA mutations, unlike the mouse model, where the burden comes from the cumulative effect of many mutations.
MitoWorld. What do you see as the next steps to follow up on this work? The next step is to introduce specific mtDNA mutations into primary cells and then add oncogenes. This will allow us to examine how individual mtDNA mutations—and their allele fractions—impact tumorigenesis. By better modeling the mutation patterns seen in human cancers, we can determine whether particular mtDNA mutations or metabolic states make cancer cells more susceptible to targeted metabolic therapies. Ultimately, this line of research could guide the development of new therapeutic strategies that exploit the metabolic dependencies created by mtDNA mutations in cancer cells.
MitoWorld. What attracted you to the study of mitochondria? As a hematopathologist, I have a strong interest in hematologic diseases, but my research has always spanned a variety of biological systems. My interest in mitochondria began during my postdoctoral fellowship in Craig Thompson’s lab, where I used red blood cell maturation as a model to study mitophagy—the process by which cells selectively remove damaged or superfluous mitochondria. That experience highlighted for me how central mitochondrial function and dysfunction are to cell biology and disease, including cancer. I am particularly intrigued by how cells sense and respond to mitochondrial dysfunction—especially when it’s caused by mtDNA mutations—and how these adaptive pathways can contribute to cancer development. Understanding the complex interplay between mitochondrial function and cellular responses not only deepens our knowledge of cancer biology but also points to new possibilities for therapeutic intervention.
Reference
Li-Harms X, Lu J, Fukuda Y, Lynch J, Sheth A, Pareek G, Kaminski MM, Ross HS, Wright CW, Smith AL, Wu H, Wang Y-D, Valentine M, Neale G, Vogel P, Pounds S, Schuetz JD, Ni M, Kundu M (2025) Somatic mtDNA mutation burden shapes metabolic plasticity in leukemogenesis. Science Advances 11(1): eads8489.
Biomedical evidence systematically collected from astronauts, mice and rats during and after extended time on the International Space, shorter trips (weeks), and even on much shorter trips such as SpaceX’s Inspiration 4 flights show mitochondrial stress.
If Elon Musk intends to plan for life on Mars or NASA plans for settlement on the Moon, they might want to consider one of the most interesting and mysterious parts of every cell in every complex organism (e.g. animals and plants), including us, mitochondria. This biological-physiological issue cannot be solved by successful SpaceX rocket launches or settlement selection. It’s not an engineering or planetary issue, but a deeply scientific and medical one.
Many scientists, philosophers, and writers have dreamed of a destiny for humanity that may exist beyond our home planet. All the global superpowers have their sites on the Moon, Mars and asteroids. Yet, the engineering, physics, material science, propulsion, planetary science and trajectories are still being mastered. In all these calculations, eventually requiring trillions in investment in engineering, there is something profoundly left out of the equation: humans and our bodies.
A MitoCast Interview with Chris Mason (WorldQuant Professor at Weill Cornell Medicine) and Afshin Beheshti (Director of Center for Space Biomedicine, Associate Director of McGowan Institute for Regenerative Medicine, and Professor of Surgery and Computational and Systems Biology at University of Pittsburgh) , top space biomedicine researchers who continue to form teams and pour over the astronaut (and mice and rat) data of those who have been in the International Space Station and on the shorter flights, tells a cautionary story, but also a focal point for countermeasures.
Listening to Mason and Beheshti, it is clear that the planned long space transits or moving off Earth will need to consider the health, function, and stress on the tiny mitochondria in each of our cells, and those of animal-nauts, which may need treatments or modifications to support life away from Earth.
Mitochondria are starting to make it into the news because of their role across the medical and health spectrum. Most people remember the biology class refrain, Powerhouse of the Cell, describing the mitochondrial role in energy production (Krebbs Cycle, ATP production). However, mitochondria, which number from 150 to 7000 per cell, depending on the tissue or organ, have deep regulatory roles in cell life and death, the immune system, and signaling in multiple ways.
Mitochondria are coming of age.
For the last twenty-years, the primary research domain has been the rare mitochondria DNA mutational diseases, primarily of childhood. However, that balance is shifting as mitochondria are now implicated in cardiac disease, diabetes, neurodegenerative diseases and in aging itself. While mitochondrial research rapidly gains ground in the search for cures for chronic diseases, health and diet, a current focus in U.S. policy, a rapidly growing parallel track runs in health and fitness circles and high-performance athletics.
Will Mitochondria Keep Us on Earth?
However, there is a certain amount of hubris to suggest that creatures specifically evolved on Earth within its gravitation, magnetic, atmospheric, biodiverse and radiation envelope would be suitable, or adaptable, to other environments, including life on the Moon or transit time to Mars. While both of those planetary objects have substantially lower gravity (Moon 1/6th, Mars 3/8th), they also either have no shielding from an atmosphere (the Moon) or very little (Mars) and have very different radiation and magnetic signatures and, of course, no known life forms.
As daunting as it was for the earliest human to migrate around the planet, chasing megafauna driven by some innate drive, leaving Earth is a very different biological, physiological and cultural challenge.
We asked Mason and Beheshti a few questions to go along with their longer MitoWorld Spotlight video.
MitoWorld: How did you end up focusing on life in Space and becoming experts in this emerging field?
Beheshti: Chris and I have been working together for almost a decade on various projects from Space biomedicine to COVID-19/Long COVID to cancer… We have had many papers in high impact journals and have put together two high profile paper packages one in Cell Press and the other in Nature Portfolio.
MitoWorld: How did you two end up working on NASA and other bio-data?
Mason: We met originally though some of the GeneLab working groups (now OSDR), working on a variety of projects for human and mouse genomics and other omics data analysis and then really to follow up on the Twins Study. This led to several sets of large-scale collaborations for the Biology of Spaceflight Cell Package in 2020, a range of papers and grants from 2019-current, and also the Nature Space Omics and Medical Atlas Resource in 2024.
Beheshti: Chris and I have been working together for almost a decade on various projects from Space biomedicine to COVID-19/Long COVID to cancer. We have had many papers in high impact journals and have put together two high profile paper packages one in Cell Press and the other in Nature Portfolio.
MitoWorld: How did you two become a team?
Mason: We kept dreaming of ways to integrate more data, leverage human and animal models for analysis, and how to engage the broader community more. We also kept making jokes during calls and enjoying each other’s company.
MitoWorld: Did NASA contract directly with you or through other entities for the work that ended up in the Omics Atlas?
Mason: We have about 12 NASA grants that have supported our work since 2014, but it was not a “contract,” but a grant, as well as NIH and NSF funding. We also had significant support from philanthropy (WorldQuant, Sloan, and Pershing Foundation)
MitoWorld: How were the writers and teams chosen to work on the key papers?
Mason: We offer a spot to everyone and anyone, but ideally get younger scientists to lead these papers and projects to help them propel their career.
MitoWorld: When did each of you become interested in life in space?
Mason: Ever since I was a kid! I went to Space Camp twice in elementary school, and loved genetics since middle school. I am grateful and honored I get to worked on the two things I love most, with people that are very enjoyable like Afshin!
Beheshti: I was always a Sci Fi fan so naturally when I started my journey with Space Biomedicine research in my second postdoc it was a great fit with my large interest in Science Fiction.
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Mason Lab Background: The Mason Lab performs research in three principal areas: (1) clinical genetics, (2) computational algorithms and data structures, and (3) synthetic biology. Clinical genetics work spans Mendelian diseases, aggressive cancers, novel viruses, and astronauts in the Space Omics and Medical Atlas (SOMA). Computational methods include new techniques in DNA/RNA sequencing, spatial imaging, planetary-scale metagenomics, and DNA/RNA base modifications. Synthetic biology research deploys new models for genome, cellular, and microbial ecosystem engineering, including synthetic T-cell systems, built environment modifications, and microbially optimized regolith. [Link]
Beheshti Background: Afshin Beheshti recently joined the University of Pittsburgh as a Professor of Surgery and Computational and Systems Biology, Director of the Space Biomedicine Program, and Associate Director at the McGowan Institute of Regenerative Medicine. In these roles, he will continue his ongoing projects and launch a new space biomedicine program at the University. With this new initiative he will create research opportunities to explore space health issues, research countermeasures to mitigate the damage caused by the space environment and develop outreach/education programs for space biology research. [link]
In a preprint article currently under review1, “Guardians of the mitochondria: Space mitochondria 2.0 systemic analysis reveals bioenergetic dysregulation across species,” a research team led by Afshin Beheshti (Director of Center for Space Biomedicine, Associate Director of the McGowan Institute for Regenerative Medicine, and Professor of Surgery and Computational and Systems Biology at the University of Pittsburgh) with co-senior author Chris Mason (WorldQuant Professor at Weill Cornell Medicine) explores the broad impacts of spaceflight on mitochondrial biology in humans and across a range of animal species to identify consistent effects of space exposure on the organelle and its influence on human health.
Astronauts returning to Earth after extended time in space suffer a number of stressors, including bone and muscle loss, cardiovascular and renal issues, circadian rhythm disruptions, potential long-term cancer risks, and ocular disorders. These health effects are thought to be caused by some combination of exposure to higher levels of radiation and reduced gravity. However, the exact mechanisms of how the conditions of space travel manifest in the physical symptoms in astronauts and other organisms are still unclear.
Previous work by Mason and Beheshti, including the “NASA Twins Study” and the “Space Omics and Medical Atlas,” measured biological characteristics in twin astronauts, Mark and Scott Kelly2 and then compared them to many additional cohorts and missions. The landmark Twins study tracked the astronauts over 340 days, while one flew on the international space station and the other remained on Earth. Surprisingly, the investigators identified mitochondrial respiration as one of the first and most important biological processes to be disrupted by spaceflight.
This new report aims to expand upon and generalize the prior findings by extracting mitochondrial function data from several studies of space exposure in a range of species, including humans (Guarnieri et al., in review). This large-scale, multi-institute study integrates an impressive collection of multi-omics data from humans, rodents, and other organisms before, during, and after returning from space. This rich dataset enables the authors to draw broader conclusions about how the mitochondria of people or animals will respond to spaceflight.
The authors show that effects of space exposure occur in a duration-dependent manner across species and tissues. More specifically, it causes accumulation of reactive oxygen species (ROS) and impairs mitochondrial oxidative phosphorylation (OxPhos), the series of enzymatic reactions that mitochondria use to extract the energy from the food we eat. Moreover, the cellular stress induced by ROS accumulation and OxPhos disruption causes the release of mitochondrial signals that trigger immune system abnormalities in astronauts and animals. Strikingly, the changes to OxPhos and immune activity are accompanied by epigenetic changes that influence mitochondrial gene expression and last for more than 14 weeks after astronauts return to Earth.
The severity of mitochondrial impairment was influenced by the genetic background of the animals exposed to the space environment. Mice with mutations leading to less robust mitochondrial antioxidant defenses against ROS experienced greater damage during space flight, suggesting certain biological pathways can be harnessed to stratify risk profiles and protect astronauts on future missions. To this end, the team tested if kaempferol, an antioxidant compound and stimulator of mitochondrial biogenesis, could reduce the damage from space exposure. Mice treated with kaempferol were protected from liver damage during spaceflight, and human liver organoids exposed to the compound in space lost less mass and retained their function, compared to their untreated counterparts.
This study differs from previous efforts in that it examines changes in mitochondrial biology in response to a range of space-exposure durations across species of animals. It emphasizes the need for and provides evidence of preventative measures and in-flight treatments that can protect astronauts from damage to their mitochondria during longer space missions. These methods and countermeasures will become more important as longer space flights are considered, and they may also shed light on Earth-bound disease mechanisms as well.
Discussion with Drs. Beheshti and Mason
MitoWorld: Space travel seems to affect multiple tissue and organ systems. Could you expand on the mechanisms underlying the effects on mitochondrial function? What work do you think should be done to better understand the conditions that lead to mitochondrial stress?
Beheshti: The two primary stressors in space that drive mitochondrial dysfunction are microgravity and space radiation. In our recent preprint, we highlight how the degree of mitochondrial disruption depends on the radiosensitivity of different tissues, suggesting that some tissues are more vulnerable than others. While both microgravity and radiation are likely to act synergistically, I believe radiation has a more pronounced and compounding impact on mitochondrial health. To better understand these mechanisms, we need studies that systematically compare the effects of microgravity and radiation, both independently and in combination. Additionally, ongoing research, including our own, is evaluating a range of mitochondrial-targeted supplements and therapies as potential countermeasures. I believe there’s strong potential to develop an optimized “mitochondrial cocktail,” a combination therapy tailored to protect against space-induced mitochondrial stress and, ultimately, safeguard astronaut health during long-duration missions.
MitoWorld: Different tissues seem to respond to space exposure in unique ways. Can you speculate on why our organs have different sensitivities to spaceflight? Furthermore, does the stress response to damage in one organ system feed forward to damage otherwise more resilient tissues?
Beheshti: As I mentioned earlier, different organs in the body have varying degrees of radiosensitivity, which helps explain why tissues respond differently to spaceflight. In our recent work, we outline how tissues, such as the spleen, skin, eyes, and immune-related organs, tend to be more radiosensitive, and denser tissues, such as muscle, bone, and brain, are generally more radioresistant. These differences have long been established in the field of radiation biology and translate well to the context of space radiation exposure. However, even the more resistant tissues are not immune. Given prolonged exposure to the space environment, we observed a widespread suppression of mitochondrial OxPhos across all tissues, including long-term effects after returning to Earth.
An important and often overlooked aspect is how damage in one organ system can propagate systemic stress. While we didn’t delve into this in the paper due to limited available data, the concept of a “bystander effect” from radiation biology is highly relevant here. This phenomenon describes how irradiated cells can transmit stress signals to neighboring non-irradiated cells, leading to secondary damage. Similar effects have been observed at the tissue level, suggesting that injury to more radiosensitive organs could exacerbate dysfunction in otherwise more resilient tissues. This kind of cascading, systemic stress response may play a significant role in how the body as a whole reacts to prolonged space exposure, and underscores the need for integrated, multi-organ studies to fully understand and mitigate these complex interactions.
Mason: Each organ system has distinct energetic requirements, and thus, we expect to see some heterogeneity in the response across tissues. Also, each organ ages at different rates, and so, this also is likely a function of mitochondrial function and complex biological interactions across multiple pathways and systems.
MitoWorld: Does mitochondrial morphology or dynamics change in the low-gravity conditions of spaceflight?
Beheshti: This is an important and still open question. At this time, we don’t have definitive data on how mitochondrial morphology or dynamics change under microgravity conditions, but it’s an area that absolutely warrants deeper investigation. In fact, we are currently conducting imaging experiments to address this very question, and we hope to provide new insights soon. Based on what we know about mitochondrial behavior under various stress conditions on Earth, I strongly suspect that mitochondrial morphology does change in microgravity. Disruptions in mitochondrial fission and fusion dynamics, alterations in cristae structure, and changes in network connectivity are all possible responses to the unique stresses of spaceflight. These changes could have significant downstream effects on energy production, redox balance, and apoptosis, ultimately impacting tissue health and resilience. Understanding these structural and functional adaptations will be key to developing targeted interventions to preserve mitochondrial health in space.
MitoWorld: It’s very interesting that the immune system is affected by mitochondrial stress induced by space flight and that epigenetic changes persist for weeks after astronauts return to Earth. Are returning astronauts more susceptible to infection after long-duration space missions, and does this pose a risk for infections threatening the viability of future space settlements and long-duration travel throughout the solar system?
Beheshti: Our findings suggest that mitochondrial dysfunction, particularly the long-term suppression of OXPHOS, plays a central role in disrupting immune function during and after spaceflight. This mitochondrial stress appears to impair the energy metabolism required for proper immune cell activation and response, leading to broader immune dysregulation. While our study highlights this link mechanistically, it raises the concern that astronauts may indeed be more susceptible to infections after long-duration missions. However, it’s important to note that direct evidence of increased infection rates in returning astronauts is still limited.
What is particularly concerning is that these mitochondrial and immune impairments persist for weeks after return to Earth, and are accompanied by sustained epigenetic changes. This suggests that the immune system does not immediately rebound post-flight, which could pose risks not only upon re-entry but also during extended missions, where access to medical intervention is limited. If such immune vulnerabilities are not properly mitigated, they could threaten the health of crew members and the overall viability of future deep space missions or permanent settlements.
Moving forward, more research is needed to directly measure susceptibility to infection post-flight and to identify reliable biomarkers that flag immune dysfunction early. We must also begin validating countermeasures, including mitochondrial-targeted therapies, that preserve or restore immune resilience in the space environment.
Mason: We don’t see longer risk of infection post-flight, but we and others do see a lot of viral activation in-flight, and changes in biological pathways related to immune function and activation.
MitoWorld: If astronauts, who are selected for being very physically fit and disciplined individuals, suffer ill health effects from long duration space travel, how would the physiological response to long-term spaceflight differ in a cross section of the population?
Beheshti: When it comes to mitochondrial dysfunction, I believe we would see similar core impacts across the general population, but the severity and resilience of the physiological response could vary widely, depending on baseline health, genetic predispositions, and other risk factors. Astronauts are among the most physically fit and medically screened individuals; yet, even they exhibit signs of mitochondrial stress, immune dysregulation, and other health effects during and after long-duration spaceflight. This suggests that members of the general population, who may have pre-existing conditions or less physiological reserve, could be even more vulnerable to the same stressors.
As Dr. Mason pointed out, the Inspiration4 mission, which was the first all-civilian crewed orbital mission, provided a glimpse into how non-career astronauts might respond to spaceflight. While it was a short-duration mission, it offered early indications that space-induced physiological changes are not limited to elite astronauts. If missions extend to months or years, as envisioned for Mars or deep-space travel, we can expect a wider range of biological responses and potentially more severe health challenges in a more diverse population.
This underscores the need for personalized countermeasures and comprehensive health monitoring tools that can accommodate a broader range of individuals. Future missions will likely include people of varied ages, health backgrounds, and genetic profiles. Understanding these differences and proactively developing adaptable therapies, particularly those targeting mitochondrial resilience, will be critical for the success and safety of long-duration human exploration throughout the solar system.
Mason: We saw that the Inspiration4 crew, which was an all-civilian crew, did just fine during a 3-day orbital mission, and so we are cautiously optimistic for future civilian crews. However, as noted above with the murine data and organ risk, the genetic background of the person and other medical factors should all be considered when assessing flight plans.
MitoWorld: This paper showed that an antioxidant and stimulator of mitochondrial biogenesis may have therapeutic benefit for astronauts. Are there any other pathways revealed by your work that you would like to target next to mitigate the damage from spaceflight?
Beheshti: Absolutely. While our study highlighted the therapeutic potential of compounds, such as kaempferol, an antioxidant and activator of mitochondrial biogenesis, our multi-omics analysis revealed additional pathways and molecular targets that warrant investigation as countermeasures. One key area involves the TCA cycle, which we found to be significantly disrupted across multiple tissues post-spaceflight, particularly at later recovery times. This dysfunction alters key metabolites, such as α-ketoglutarate and succinate, that compromise energy metabolism and act as epigenetic regulators, influencing long-term gene expression patterns.
We also observed suppression of mitochondrial protein import machinery (e.g., TOMM20, CHCHD4), MT-ribosome biogenesis, and Fe-S cluster biosynthesis—critical components for maintaining mitochondrial integrity. These are promising intervention points. Another major axis of dysfunction involves sustained activation of the HIF-1α/mTOR pathway, which shifts cellular metabolism from OXPHOS toward glycolysis in a maladaptive response to stress. Targeting this metabolic rewiring could help preserve energy efficiency and reduce cellular senescence.
Additionally, our work showed that mitochondrial damage leads to the release of DAMPs, such as mtDNA and mtdsRNA, which chronically activate innate immune responses (e.g., via cGAS-STING, NLRP3, and RIG-I/MDA5 pathways). This immune dysregulation could be addressed through strategies that reduce mtDAMP release or block downstream inflammatory cascades.
Beyond antioxidants, we’re also exploring:
- SOD2 mimetics (e.g., MnTBAP, EUK8) to reduce oxidative damage,
- MicroRNA-based therapeutics (targeting miR-16-5p, miR-125b-5p, and let-7a-5p),
- PGC1α activators, such as epicatechin or TFEB/NRF1 inducers, and
- regulators of mtDNA replication and repair, including POLG co-factors.
These approaches offer a systems-level path forward. We’re now working to identify synergistic combinations, a kind of “mitochondrial cocktail,” to simultaneously stabilize bioenergetics, dampen inflammation, and promote mitochondrial renewal. These countermeasures are critical for astronaut health during deep space missions and for understanding and treating age-related mitochondrial decline here on Earth.
MitoWorld: You examined an extraordinary number of systems in this paper. What might be the next steps to follow up on this study?
Beheshti: This study was an ambitious effort to map systemic mitochondrial dysfunction across species, but it’s just the beginning. The next logical step is to expand these investigations into additional models that more closely simulate the conditions of deep space, particularly with higher radiation doses and longer exposure durations. These environments will allow us to better assess how prolonged mitochondrial suppression impacts organ function, immune resilience, and aging-like phenotypes.
Equally important is advancing the development and testing of mitochondrial-targeted countermeasures. While our results with kaempferol are promising, a broader, more systematic approach is needed. This includes evaluating combinations of antioxidants, metabolic modulators, gene expression regulators, and mitochondrial biogenesis enhancers across multiple tissues and models. I believe we’re on the cusp of identifying an optimal therapeutic mitochondrial cocktail that could protect against the chronic stressors of spaceflight.
I also want to take this opportunity to invite the broader mitochondrial and space biology communities to join us. Collaboration will be essential to accelerate the development of effective interventions. This is an open call. If you’re working on relevant pathways or therapeutics, let’s connect and build a coordinated strategy to move this field forward together.
Finally, space provides a unique and accelerated model of mitochondrial disease. The dysfunctions we observed in astronauts mirror and, in some cases, intensify those seen in patients with mitochondrial disorders. If we can validate countermeasures that work under the extreme conditions of space, there’s a strong potential to translate those findings back to Earth and develop novel treatments for patients suffering from mitochondrial diseases and related chronic conditions.
Mason: Replication is the cornerstone of good science, and so we want to continue to test these models in future missions, other animal cohorts, and in other cellular contexts.
MitoWorld: Aging induces changes in mtDNA over time and causes changes in the ratio of healthy mtDNA to damaged mtDNA, known as heteroplasmy. Would it be wise in future studies to look at heteroplasmic shifts and if they are permanent or seem to rebound once astronauts return to Earth?
Beheshti: Yes, indeed it will be. We have plans to further explore this.
Mason: Yes, we have seen some evidence of this already from prior missions, and this is an exciting area for future study.
References
1Guarnieri JW, Maghsoudi Z, et al. Guardians of the mitochondria: Space mitochondria 2.0 systemic analysis reveals bioenergetic dysregulation across species. Cell In review.
http://dx.doi.org/10.2139/ssrn.5087025
2Garrett-Bakelman FE, Darshi M, Green SJ, Gur RC, Lin L, Macias BR, McKenna MJ, Meydan C, Mishra T, Nasrini J, Piening BD (2019) The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight. Science 364(6436): eaau8650.
Do neurons help cancer spread? In a paper published in Nature, a multi-institution research team, led by Simon Grelet at the University of South Alabama, provides strong evidence for a key relationship between cancer cells and neurons. They showed that mitochondria migrate from neurons to cancer cells to increase the metabolism of the cancer cells.
Dr. Grelet’s team focused on the mitochondria in cancer cells. The spread of tumors requires a significant amount of energy, and mitochondria produce energy for the cells. Cancer cells are well-known for adapting their metabolism to fit changing conditions. However, this metabolic plasticity was thought to be due to changes within the tumor cells themselves. For example, they could obtain energy by glycolysis (a less efficient process for producing ATP in the cytoplasm) or by oxidative phosphorylation (a more efficient process in the mitochondria). However, cancer cells also receive outside help in the form of metabolites, growth factors and cytokines from other cells.
Previous experiments had shown that somehow the neurons aid tumor progress, but what really interested the Grelet team was a relatively new concept that mitochondria can move from cell to cell. When neurons were co-cultured with tumor cells, the neurons experience changes to their metabolism. The number of their mitochondria increases, and some are transferred to the tumor cells. How could this work?
The team first looked at a co-culture of an aggressive breast cancer cells and neurons. The neurons underwent a morphological change from globular to tubular structures, which indicated the cancer-induced differentiation of the neurons. Neuronal differentiation is associated with changes of metabolic programming from glycolysis to oxidative phosphorylation. These changes were also associated with the establishment of long neuron protrusions, forming a neural network in the culture in vitro, which reflects the establishment of a nerve-cancer crosstalk and suggests the communication or sharing of biological materials.
Next, the team used fluorescent-labeled mitochondria to show that the mitochondria migrated from neurons to cancer cells. These methods revealed additional insights into the transfers, but they had significant limitations. To overcome those limitations, the team developed MitoTRACER. This system used genetic engineering where the donor cell mitochondria carry a tag protein that, once transferred to the recipient cells, triggers an enzymatic reaction activating the permanent expression of a fluorescent protein. The trick is that, when mitochondria move from the neurons to the cancer cells, the red fluorescence is lost, and a green signal is permanently activated. Thus, it is easy to monitor cells with mitochondria that have migrated into a new cell.
Using this unique approach, the researchers have been able to investigate the fate of the recipient cells during the cancer progression cascade, and by fate mapping of the recipient cells from the primary tumor during metastasis progression in vivo. The researchers noted enrichment of acquired mitochondria in brain metastases that might indicate enhanced metabolic plasticity from those extra mitochondria. Neuronal mitochondria are more metabolically active and might better enable tumor cells to thrive in the brain environment. This approach allowed us to define the role of mitochondrial transfer in the primary tumor environment. This process generates a subset of highly efficient metastasis cells that succeed through the complex stops and that are resilient to the metastatic barriers to ultimately form distant metastases, which is the main driver of cancer-associated mortality.
In summary, this fascinating paper might have significant implications for future cancer therapies, and beyond the cancer context, the mitoTRACER approach could have broader applications in studying cell-cell transfer of mitochondria in health and disease to understand the physiopathological implications of these transfers better.
Discussion with Dr. Grelet
MitoWorld: Your paper brings to mind the work of Judah Folkman who showed that tumors need and encourage the formation of a blood supply to progress. What do you believe the tumor may be getting from the nerve cells?
Interesting comparison. Yes, there are definitely commonalities between cancer angiogenesis and cancer innervation. In fact, cancer can actively “call” neurons to innervate them. In the context of cancer, we recently showed that aggressive subtypes of breast cancer cells can secrete axon guidance molecules, including Semaphorin-4F, to promote cancer innervation. We also found that this increased nerve density is associated with enhanced metastasis (PMID: 34810279).
The role of axon guidance molecules in promoting cancer innervation was demonstrated years ago by Dr. Gustavo Ayala (PMID: 11746267; PMID: 24097862), who pioneered the field of cancer innervation and collaborated with us on this study. Since then, many studies, including our own, have confirmed the contribution of these molecules to cancer innervation and cancer aggressiveness. While increased nerve density is often associated with poor clinical outcomes, the underlying mechanisms have remained poorly understood. This gap in understanding is precisely what motivated us to conduct this study.
MitoWorld: The movement of mitochondria from cell to cell is still controversial. What do you think it will take to solidify the concept?
The idea of intercellular mitochondrial transfer remains controversial, largely due to the lack of robust tools and clear in vivo evidence. To solidify the concept, new rigorous and physiologically relevant approaches are needed. For example, genetic systems, such as our MitoTRACER approach, which allow for precise and conditional signaling of transfer events, open the avenue for lineage-based tracking of transferred cells in vivo. Such models are critical to move the field forward and to convincingly demonstrate that mitochondrial transfer is not merely an artifact, but a biologically meaningful process.
MitoWorld: How do you think the cells signal to each other to initiate the transfer of mitochondria?
A variety of signals could potentially be involved in initiating mitochondrial transfer, but these remain to be better defined. In the context of cancer innervation, axon guidance molecules may contribute; more generally, transfer events may occur as part of a stress or help response, or by hijacking existing physiological communication routes. These signals could include reactive oxygen species, cytokines, or changes in membrane potential or lipid composition. Cancer cells, for instance, can upregulate molecules involved in cell-cell contact to facilitate mitochondrial transfer, as elegantly demonstrated by Watson et al. (PMID: 37169842). Deciphering the molecular language of this intercellular request remains a critical next step for the field.
MitoWorld: These experiments seem to have ramifications for how the nuclear and mitochondrial genomes coordinate their activities. Do you think the communication between the donated mitochondria and the recipient cell also involves the donor genes?
Absolutely, and this is a topic that warrants further investigation. Mitochondrial transfer introduces not only a new metabolic organelle with all its associated machinery, but also foreign mitochondrial DNA into the recipient cell, raising important questions about nuclear–mitochondrial coordination. While the nuclear genome of the recipient cell continues to govern most mitochondrial functions, the donor mitochondria carry their own genome and organelle machinery, which in our case is fine-tuned for neuronal metabolism and may not be fully compatible. This mismatch could influence mitochondrial gene expression, protein stoichiometry, and ultimately, the bioenergetic output. Whether donor mitochondrial DNA or its transcripts actively modulate recipient cell behavior remains an open and fascinating question. Clarifying the extent and mechanisms of this intergenomic crosstalk is essential to fully understand the consequences of mitochondrial transfer.
MitoWorld: You note that more work is needed to determine if the effects of the donated mitochondria are related to metabolic efficiency or simply that there are more of them. Do you have any sense of which it might be?
In the context of neurons, it is likely a combination of both abundance and quality. On one hand, the increase in mitochondrial mass may help support basic energy demands, particularly under stress. On the other hand, the quality and origin of the donated mitochondria, such as their neuronal bioenergetic efficiency, may actively contribute to metabolic reprogramming in the recipient cell. In our system, the integration of neuronal mitochondria appears to enhance not only energy production but also metabolic plasticity, enabling cancer cells to better adapt to new microenvironments. Dissecting the relative roles of mitochondrial abundance versus functional impact will be key to understanding how mitochondrial transfer influences cell fate and behavior.
MitoWorld: Folkman used his findings to suggest that cancers could be treated by preventing angiogenesis, and that is now widely accepted. Do you have any thoughts on how your findings with neurons might be used to develop therapeutic strategies for cancer?
Yes, absolutely, that is the ultimate goal. There are several possible strategies. First, we can target tumor innervation itself, which supports cancer progression. Second, we can aim to block the intercellular transfer of mitochondria, which fuels cancer cell adaptation. Third, and perhaps most compelling, we can selectively target recipient cancer cells that have acquired unique metabolic or phenotypic traits as a result of mitochondrial uptake. These cells may represent a vulnerable subpopulation that could be eliminated through precision therapies. Together, these approaches offer a new framework for tackling cancer’s adaptability.
MitoWorld: You looked at breast cancer and melanoma cells, both highly metastatic cancer types. Is the neuronal connection equally valid in less metastatic cancers?
We also previously reported a link between cancer plasticity and cancer innervation (PMID:37046688). Our findings suggest that more aggressive cancer cells are more likely to establish neuronal connections and engage in mitochondrial transfers. This, in turn, may further amplify their aggressive behavior, creating a vicious cycle. The ability of these cells to co-opt neural signaling and reshape their metabolic and phenotypic programs reflects a high degree of plasticity that likely contributes to disease progression.
MitoWorld: Also your work focused on solid tumors. Is there anything to be learned about blood tumors?
Interesting point. Blood cancers reside in richly innervated niches, such as the bone marrow, where neurons regulate hematopoiesis and immune responses. So, similar mechanisms might shape the behavior of leukemia or lymphoma cells. However, this remains largely unexplored, and adapting lineage-tracing tools, such as MitoTRACER, to hematological models could open exciting new directions in the field.
Reference
Hoover G, Gilbert S, Curley O, Obellianne C, Lin MT, Hixson W, Pierce TW, Andrews JF, Alexeyev MF. Ding Y, Bu P, Behbod F, Medina D, Chang JT, Ayala G, Grelet S (2025) Nerve-to-cancer transfer of mitochondria during cancer metastasis. Nature
Dr. José Antonio Enríquez—known to his lab simply as Toño—leads the Functional Genetics of the Oxidative Phosphorylation System (GenOXPHOS) group at the Spanish National Centre for Cardiovascular Research (CNIC). Using large-scale bioinformatics, his lab investigates many aspects of mitochondria, including how their protein complexes assemble, the pathophysiology of mitochondrial diseases, and even the evolutionary history of mitochondrial proteins.
Toño’s path to mitochondrial science began at the University of Zaragoza, where he completed his PhD. He then moved to California for a postdoc at Caltech before returning to Zaragoza to establish his first lab as a Principal Investigator. About 15 years ago, he moved his lab to CNIC, where he continues to push the boundaries of mitochondrial biology.
When asked what drew him to this field, Toño recalled:
“When I finished my biology degree, I knew I wanted to dedicate my life to science, but my interests were broad. I wasn’t drawn to one specific topic or focused on curing a particular disease. I was more interested in understanding the logical rules behind life itself. During a lab rotation at the University of Zaragoza, I encountered mitochondrial DNA (mtDNA). I was fascinated by the fact that this tiny but essential chromosome lives outside the cell nucleus. The idea of an ‘outsider’ chromosome inside a eukaryotic cell sparked my curiosity, and that’s what brought me to mitochondrial research.”
Known for his passionate and fiercely curious nature, Toño fosters a lab culture that encourages creativity, independence, and open scientific debate. He pushes his lab members to think outside the box—not just in their experiments, but in how they approach problems, question assumptions, and imagine what might be possible. He thrives on “crazy” ideas and welcomes disagreement as a sign of engaged thinking. Weekly lab meetings often begin with him sharing a new paper, a philosophical question, or a hypothesis that came to him out of the blue.
What are the big questions ahead for mitochondrial research?
“Mitochondria continue to surprise us,” says Toño. “From their own unique DNA and divergent genetic code to their roles in apoptosis, signaling, and disease, there’s always something unexpected. The OxPhos system alone is remarkably complex in both structure and function.”
As for what’s coming next?
“I think the most important discoveries may still be ones we don’t expect. But if I had to name specific questions for the coming year, I’d point to three:
- Understanding how sodium (Na⁺) helps build the mitochondrial membrane potential,
- Figuring out how cells maintain different types of specialized mitochondria within a single cytoplasm, and
- Resolving the debate over whether mitochondria can move between cells in a physiologically meaningful way.”
A major breakthrough: SCAF1 and mitochondrial supercomplexes
One of the lab’s most exciting discoveries was identifying the protein SCAF1 (supercomplex assembly factor 1), which enables the physical interaction between two key components of the electron transport chain—complex III and complex IV.
“This was a big step in supporting our ‘plasticity model’ of how the mitochondrial electron transport chain is organized,” says Dr. Enríquez. “We were also excited to show that variations in mtDNA can influence metabolism and healthy aging. And our recent finding that respiration complex I acts as a sodium/hydrogen (Na⁺/H⁺) antiporter revealed that sodium plays a major role in building the mitochondrial membrane potential.”
Meet the GenOXPHOS Team:
The GenOXPHOS lab currently includes around 10 members, each pursuing their own research, but generally, the group can be divided into the following research directions.
Mitochondrial Supercomplexes and Their Role in Health
This team includes three graduate students, each using different strategies to understand how respiratory supercomplexes are assembled and what role they play in health and disease.
Carmen Morales Vidal studies a highly conserved supercomplex made up of respiratory complexes I and III, exploring the importance of this interaction in mammalian cells.
Paula Fernández-Montes Díaz focuses on a family of complex IV protein isoforms, each of which is responsible for a different conformation of complex IV. These variants allow tissues to fine-tune their metabolism based on specific energy needs.
Sara Natalia Jaroszewicz specializes in advanced super-resolution microscopy to visualize these supercomplexes inside intact cells. Until recently, this was only possible using indirect and often disruptive methods.
Heart-Specific Mitochondria
Located in a cardiovascular research center, the lab has a strong focus on heart-specific mitochondrial biology.
Dr. Michaela Veliova, a postdoctoral researcher, studies different subtypes of mitochondria within individual heart cells. She’s investigating how these subtypes form and function and what roles they play in disease.
Dr. Rebeca Acín, a senior scientist, examines the reversal of ATP synthesis, a process where ATP synthase (normally making ATP) starts breaking it down. While this may help with mitochondrial quality control, Rebeca is exploring its connection to disease. She’s also investigating how ATP synthase dimerization (its ability to form pairs) affects this reversal process.
Translational Research: From Discovery to Therapy
This part of the lab focuses on translating basic mitochondrial science into potential therapies.
Dr. Marta Pérez-Hernández Durán, a postdoctoral researcher, is studying a protein kinase called FGR that regulates the activity of mitochondrial complex II. Stress-dependent activation of FGR increases reactive oxygen species (ROS) production and stabilizes HIF1a, ultimately leading to increased release of inflammatory cytokines. Since inflammation is present in numerous heart diseases, Marta is testing whether blocking FGR could be a promising treatment.
Dr. Rebeca Acín is exploring another potential drug target. OMA1, a stress-activated mitochondrial protease can trigger fragmentation of mitochondria. She is examining whether modulating its activity could help prevent mitochondrial damage in disease.
Bioinformatics and Structural Modeling
This line of research seeks to uncover how mitochondrial structures and genetic interactions shape function and dysfunction.
Dr. Jose Luis Cabrera Alarcón, a postdoctoral researcher, studies evolutionary conservation of mitochondrial genes at the population level, with the aim of identifying how genetic incompatibilities between nuclear and mitochondrial genomes might contribute to disease.
Marina Rosa Moreno, a graduate student co-mentored by Dr. Enriquez and José Luis, studies the structural biology of respiratory chain complexes. Using computational modelling and cryo-electron microscopy, she investigates how the respiratory chain complexes assemble and how structural variations may affect energy production and pathology.
The Lab’s Backbone
A great research environment doesn’t just depend on bold ideas. It also relies on the people who keep things running. GenOXPHOS is supported by a dedicated technical team:
Dr. María Concepción Jiménez Gómez, the lab manager, keeps operations smooth and organized.
Eva Raquel Martínez brings deep expertise in histology and molecular biology techniques.
Dr. Raquel Martínez de Mena oversees tissue culture and cell maintenance.
María del Mar Muñoz Hernández, the lab’s mouse technician, specializes in advanced animal procedures critical for the in vivo and translational work.