In a paper published in Cell, the laboratory of Isha Jain at Gladstone Institutes showed that a small molecule inhibitor can control excess oxygen levels resulting from dysfunctional mitochondria. These results point to a potential new therapeutic strategy for mitochondrial diseases.
Oxygen is well-known to be critical for human life, but too much oxygen can be toxic. Thus, the balance between supply and demand is important. For most of us, that is no problem. However, that careful balance is disrupted in those with some mitochondrial diseases so that excess oxygen is a common feature. Leigh syndrome is the most common pediatric mitochondrial disease.
Since tissue hyperoxia is problematic in these patients, one might wonder if reducing the concentration of oxygen in tissues would be beneficial. A recent study from the laboratory of at Gladstone Institutes and the University of California, San Francisco showed just that. The team, led by Isha Jain, took advantage of mice with a knockout of the Ndufs4 gene (Blume et al., 2025). That mutation results in the loss of an important complex in the electron transport chain that mimics the disease, and these mice are often used as a model for experimentation.
They exposed the mice to a small molecule called HypoxyStat that induces hypoxia by causing oxygen to bind more tightly to hemoglobin, leading to decreased release of oxygen into tissues. Chronic exposure of the mice to the molecule normalized tissue hyperoxia and resulted in significantly longer lifespans in the mice.
Thus, these findings suggest that drugs, such as HypoxyStat, that lower effective oxygen levels might be a promising therapeutic strategy for these diseases in general. Of course, manipulating oxygen levels is challenging, but these results provide valuable insights into mitochondrial diseases.
A video, Science in Seconds, produced by Gladstone tells the story of Jain and her team’s breakthrough, as does an article, Daily Drug Captures Health Benefits of High-Altitude, Low-Oxygen Living, published by Gladstone on the findings.
An interview with Dr. Isha Jain
Do the benefits result from improved mitochondrial function or the reduction of excess oxygen in tissues or both?
Currently, I would say we have the strongest evidence that the benefit occurs due to the alleviation of tissue hyperoxia (excess oxygen) in tissues. Future work is needed to fully understand the mechanism.
You noted that you wanted to determine if you could generalize your results beyond the Ndufs4 mice. What do you see as the next steps in this research?
The next steps include testing whether this compound (or further optimized compounds) work in additional mitochondrial disorders and additionally affected tissues beyond the brain.
Mitochondria have been around for a very long time, and oxygen levels have fluctuated in our atmosphere. Does that mean that mitochondria have adapted to the available oxygen?
It is indeed puzzling that oxygen is both a substrate and a toxin for mitochondrial ATP production. It appears that we have evolved to exist in a very delicate balance of too little or too much oxygen.
The findings are intriguing, but controlling oxygen levels might be a challenge in patients. For example, are those with mitochondrial diseases, such as Leigh syndrome, affected by changes in altitude (e.g., Denver)?
There is anecdotal evidence that this might be the case. However, mitochondrial diseases are rare enough and the altitudes we are talking about are fairly high, so it is difficult to amass enough epidemiological data to make this claim definitively.
You mention pulmonary hypertension as a complication of using drugs, such as these. Are there other potential complications and ways around the problems?
The side effects are the same as living at altitude: things like pulmonary hypertension and increased blood viscosity. A gradual acclimation to the drug (dose escalation) will likely be needed. Many more safety studies are needed before this compound or related compounds can be used in patients.
What initially interested you in the study of mitochondria?
I am broadly interested in developing creative new therapies for metabolic disorders. Of course, mitochondria are where much of metabolism takes place.
Reference
Blume SY, Garg A, Martí-Mateos Y, Midha AD, Chew BTL, Lin B, Yu C, Dick R, Lee PS, Situ E, Sarwaikar R, Green E, Ramanan Y, Grotenbreg G, Hoek M, Sinz C, Jain IH (2025) HypoxyStat, a small-molecule form of hypoxia therapy that increases oxygen-hemoglobin affinity. Cell https://doi.org/10.1016/j.cell.2025.01.029.
Ryu KW, Fung TS, Baker DC, Saoi M, Park J, Febres-Aldana CA, Aly RG, Cui R, Sharma A, Fu Y, Jones OL. Cai X, Pasolli HA, Cross JR, Rudin CM, Thompson CB (2024) Cellular ATP demand creates metabolically distinct subpopulations of mitochondria. Nature 6: 1–9.
You see one; you’ve seen them all. That has been pretty much the view of mitochondria for some time. But maybe that isn’t the case after all. The laboratory of Craig Thompson reports that, under stress conditions, mitochondria assume different roles. Dr. Thompson is the former president of Memorial Sloan Kettering Cancer Center and currently holds the Douglas A. Warner III Chair in the Cancer Biology and Genetics Program.
Dr. Thompson’s research team began their search with a careful rethinking of mitochondrial functions. While mitochondria have many key functions, they are best known for producing the energy that we all need from the food that we eat. However, the Thompson lab was interested in the role of mitochondria in wound healing. Repairing tissue requires energy and also proteins, lipids, nucleic acids and other biomolecules. Thus, part of our food goes for the raw materials to synthesize new biomolecules to repair and/or maintain our tissues. They discovered that the amino acid proline is critical for wound healing and that the mitochondria are important for its synthesis.
With that discovery, they became curious about how the mitochondria balance their efforts to make energy and proline. As often happens in science, a few simple experiments conducted by changing the cell culture conditions left them with even more questions. The cells seemed to be able to both make energy and raw materials at the same time. How could that be?
To tackle that question, they exposed cells to 2 different sets of stresses. In one set cells were made to need more ATP, and in the other to need more proline. Surprisingly, when cells were deprived of proline, some of the mitochondria changed their morphology. They developed a series of filaments within the inner membrane that increase their ability to make proline and ornithine. When cells needed more ATP their mitochondria also separated into two distinct subpopulations. In fact, the two types of mitochondria could be differentiated by simple microscopy. The bonus finding was that an enzyme called pyroline-5-carboxylate synthase or P5CS was the key to how glutamate was used to yield the two types.
The separation of activities is closely related to the ability of mitochondria to fuse together and separate by fission. When the cell’s need for oxidative synthesis increases, P5CS is segregated into a subset of mitochondria that lack cristae and ATP synthase, the enzyme that makes ATP.
Thus, the mitochondria can easily rearrange themselves to focus on one process or the other. Interfering with the fission-fusion cycle inhibits their ability to specialize. This paper shows that mitochondrial fission and fusion are intimately involved in maintaining the balance between the need for energy and synthesis of biomolecules.
Reference
Ryu KW, Fung TS, Baker DC, Saoi M, Park J, Febres-Aldana CA, Aly RG, Cui R, Sharma A, Fu Y, Jones OL. Cai X, Pasolli HA, Cross JR, Rudin CM, Thompson CB (2024) Cellular ATP demand creates metabolically distinct subpopulations of mitochondria. Nature 6: 1–9.
According to the CDC, about 38 million Americans suffer from diabetes, and it is the fourth leading cause of death in the United States. More concerning is that the incidence of diabetes—especially type 2 (T2D) or adult-onset diabetes—is increasing.
Diabetes is caused by the inability of pancreatic b-cells to make or other cells to use insulin. An autoimmune process has long been suspected to be involved. Skeletal muscle and b-cells in patients with T2D have multiple morphological and functional defects.1,2
Recently, a team of researchers at the University of Michigan explored this mitochondrial dysfunction and showed how it might be linked to diabetes.3 The team, led by Scott Soleimanpour, MD and Emily M. Walker, PhD, examined mitochondrial quality control that maintains appropriate mitochondrial function under stress conditions. More specifically, they looked at three pathways that lead to impairments in mitochondrial quality control: decreased mitoDNA levels, preventing elimination of damaged mitochondria, and inhibition of mitochondrial fusion. The initial experiments were done in mice, but the findings were repeated in human pancreatic islet cells.
Interestingly, the result was the same for all three pathways. In all cases, the stress response resulted in interference with the maturation of b-cells. Blocking the stress response allowed them to mature as normal. Thus, these insights suggest that blocking the stress response might be a beneficial therapeutic strategy.
A conversation with Dr. Walker.
T2D is linked to diet. Do your results offer any insight into that link?
In two of our models of impaired mitochondrial quality control, the animals were placed on a high-fat diet to model individuals eating a western-style diet. We saw a much stronger stress response and loss of b-cell maturity when the animals were on this diet. There are a lot of negative impacts for b-cells when they are required to produce more insulin to compensate for weight gain, and also, there are many studies showing that fatty acids themselves damage b-cells. In our study, the high-fat diet sped up the mitochondrial stress responses likely because of this increased damage due to the food they were eating.
Can you speculate on the nature of the signaling molecules that illicit the response?
Our study found that it was the integrated stress response that includes changes to signaling molecules, such as eIF2α, and a transcription factor called ATF4. Activation of this signaling pathway and these factors induced changes in the nucleus that changed what genes were expressed in both b-cells and liver cells. We saw increases in the stress response target genes and decreases in genes that help the cell to have mature function and identity.
Your results provide a window on the process of normal b-cell development. Do you have any thoughts on those mechanisms?
We know that b-cells need proper mitochondrial function to maintain cell maturity. We also know that, during differentiation of stem cells into b-cells, this doesn’t happen in a complete way. Other work in our lab is focused on how to improve mitochondrial function in stem cell-derived b-cells to help them mature better, and we’re just starting to figure out pathways that can help this happen.
The use of ISRIB to block the stress response is an intriguing result. Is that a viable possibility for a therapy?
Clinical trials for next generation drugs related to ISRIB are being performed to treat different diseases, including ALS. Additionally, another group has investigated the benefits of ISRIB on reducing the immune cells involved in type 1 diabetes. We are interested in following up on potential positive effects of ISRIB, or newer versions of the drug, on islets from T2D donors.
What do you see as the next steps in this research?
Our next steps include what I mentioned above in relation to inhibiting the integrated stress response (with ISRIB or other drugs) and seeing if they positively affect T2D donor islets. We would also like to determine if our findings in liver are applicable to human disease, such as metabolic dysfunction-associated steatotic liver disease.
What interested you in mitochondria in the first place?
We grow up learning about how mitochondria are the “powerhouse of the cell,” but what is really fascinating is that mitochondria do a whole lot of other things in the cell besides just making energy. In this work, we’ve shown that they can actually signal to the nucleus and change the way the DNA is packaged to make certain genes turn off and on! Because metabolism is so important to a cell, it’s really interesting to figure out how exactly the mitochondria direct changes in ways far beyond energy production.
References
1Flannick J, Mercader JM, Fuchsberger C, et al. (2019) Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature 570: 71–76.
2Lowell BB, Shulman GI (2005) Mitochondrial dysfunction and type 2 diabetes. Science 307: 384–387.
3Walker EM, Pearson GL, Lawlor N, et al. (2025) Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues. Science. DOI: 10.1126/science.adf2034
Lee RG, Rudler DL, Raven SA, et al. (2024) Quantitative subcellular reconstruction reveals a lipid mediated inter-organelle biogenesis network. Nature Cell Biology 26: 57–71.
www.nature.com/articles/s41556-023-01297-4
To survive, cells rely on collections of organelles, such as mitochondria, endoplasmic reticulum, peroxisomes, Golgi apparatus, and more. Each has specific critical functions. However, they don’t work in isolation. They interact by communicating signals and exchanging materials in an orderly manner. Amazingly, little is known about how they interact.
The laboratory of Aleksandra Filipovska used an innovative strategy to explore the interrelationships of several key organelles with mitochondria. They first established cell lines that lacked genes specific for the production of peroxisomes, Golgi, and ER with mitochondria. Then they combined observations by scanning electron microscopy with multi-omics profiling to examine the RNAs, proteins, lipids, and glycogens that were affected by the perturbations. In this way, they could carefully examine how dysfunction in one organelle affected the mitochondria.
Because mitochondria influence so many cell activities, it wasn’t surprising that the researchers found effects in many systems. However, they found that lipid transfers were the most affected component. This very complete paper documents the many metabolic and morphological interactions within cells and provides insights into how they might be involved in diseases.
Questions for Dr. Filipovska
Congratulations on a tour-de-force paper! Your strategy here seems to be an interesting variation on the systems biology: eliminate one component and see what happens. Has anyone else tried this strategy?
Thank you! This specific strategy of genome-wide screening coupled with FIB-SEM imaging and quantification has not been tried previously, to the best of our knowledge. One of the reasons we decided to pursue this strategy was to get an unbiased account of inter-organelle interactions and changes as opposed to traditional targeted analyses.
Your calculations on the number of genes that might be involved in inter-organelle dysfunctions and diseases large enough to be concerning. How do you read that?
We were quite surprised to see so many gene changes, and in addition to the genes reported in Lee et al., we have also analyzed many more that are involved in inter-organelle communication and metabolite exchanges. These numbers are starting to make a lot of sense to us now, given how many of these genes are involved in metabolic and biogenesis pathways that are shared across different organelles. For example, the glycerophospholipid pathway spans the endoplasmic reticulum, Golgi apparatus, mitochondria and peroxisomes. Systems biology methods are key to understanding changes across different organelles, providing a larger picture of metabolic processes and common dysfunctions that manifest in different diseases.
You gave a small hint about future experiments to look at tissues under different metabolic demands near the end of the Discussion. Could you expand on that a little?
We are particularly interested in understanding the tissue-specific defects in multi-systemic diseases, such as mitochondrial diseases where a common molecular defect can manifest in different pathologies depending on the affected tissue in a particular disease. This will enable us to design targeted therapeutics for specific organs. Our study also revealed that different molecular defects can cause mitochondrial dysfunction and that targeted treatments of mitochondrial dysfunction may help alleviate symptoms of other diseases that involve mitochondria.
How did you become interested in mitochondria in the first place?
As an undergraduate student, I became fascinated by the bacterial origin of mitochondria and how they retained a level of autonomy within eukaryotic cells, maintaining a very small genome that is essential for life. At the time, very little was known about the regulation of mitochondrial gene expression, despite the many diseases for which there were no cures or treatments that were caused by defects in the mitochondrial genome. I was inspired to understand how the small mitochondrial genome was regulated that could help identify much needed therapies for mitochondrial diseases that are devastating for the patients, often very young infants and children and their families. I started my career trying to modify the mitochondrial genome and find gene therapies, which of course at the time did not work, and the main reason for this was that there was so little known about the mitochondrial genome, transcriptome and proteome. My goal was to focus on understanding the regulation of the mitochondrial genome in my group to help us devise specific therapies for mitochondrial diseases.
Reference
Lee RG, Rudler DL, Raven SA, Peng L, Chopin A, Moh ES, McCubbin T, Siira SJ, Fagan SV, DeBono NJ, Stentenbach M, Brown J, Rackham FF, Li J, Simpson KJ, Marcellin E, Packer NH, Reid GE, Padman BS, Rackham O, Filipovska A (2024) Quantitative subcellular reconstruction reveals a lipid mediated inter-organelle biogenesis network. Nature Cell Biology 26: 57–71.
Mitochondria have been linked to multiple diseases and aging. Unlike other cellular organelles, mitochondria contain their own DNA, and that DNA can be damaged or mutated so that it no longer functions correctly. A cell might contain up to 1000 copies of the mitochondrial DNA (mtDNA), and the copies might be a mixture of mutated and wildtype mtDNAs, a state known as mtDNA heteroplasmy.
A disease is manifested only if there are too few wildtype copies to maintain normal function. Until recently, few if any treatment options were available.
The discovery of genome editing has initiated a new era of possibilities. However, translating it to living organisms is challenging. Now a group of researchers, led by Carlos Moraes at the University of Miami, applied genome editing to a mouse model of mitochondrial disease.1 These mice are heteroplasmic for a mutation in the gene for the alanine transfer RNA. Thus, the researchers used a cytosine base editor to insert a compensatory edit into the mtDNA. That edit restored the tRNA function by allowing it to reassume its native stem-loop structure. However, at higher doses, off-target editing of mtDNA occurred, emphasizing the need for more precise editing.
These exciting results indicate that genome editing may be a useful therapeutic strategy for treating the previously intractable mitochondrial disorders and that additional research efforts would accelerate the translation of these approaches to the clinics.
Discussion with Dr. Carlos T. Moraes
Your work is the first to use this technique in vivo. What are the challenges to expanding this strategy?
MtDNA base editing has been used mostly to create mtDNA mutations. There are very few mouse models of mtDNA mutations, and even the one we used could not be directly corrected with the approaches available when we started the project.
It is encouraging that your strategy worked in multiple mouse organs, but in a practical sense, is it really scalable to mitochondrial diseases in large organs, such as skeletal muscle?
As in any gene therapy approach, the bottle neck is the ability to deliver genes to the desired organ. Muscle is actually a good target, as AAV viruses have been shown to deliver genes to muscle after intravenous injections. The brain is a bit more difficult.
In your experiment, the disease mutation was well known. Is that true of other diseases or will potential application of your method have to await elucidation of those mutations? This is not meant as a criticism. It’s just a question about expanding its application in the future.
We are very good at detecting disease mutations these days. However, each mutation would require a specialized base editor, which could make the treatment expensive.
Do you have any thoughts on how to reduce the number of off-target edits?
Work around the world is focusing on this question. Some mutations in the base editors have already improved the ratio of on-target/off-target, but further experimentation will be required.
What mitochondrial diseases are the “low-hanging fruit” that might be cured or treated with gene editing?
There are basically two modalities of mtDNA gene editing: 1) mitochondrial nuclease. These cut specifically mutant mtDNA. Precision Biosciences is gearing up for clinical trials on the m.3243G mutation, targeting skeletal muscle. 2) Base editing, as reported in our publication. This maybe more appropriate for homoplasmic mutations, such as Leber hereditary optic neuropathy. These can be treated by AAV injection of the base editor gene into the eye.
How did you first get interested in studying mitochondria?
I have been studying mtDNA disease since my PhD, starting in 1987, at the time where the first mtDNA mutations in patients were described. 38 years and counting!
Reference
1Barrera-Paez JD, Bacman SR, Balla T, Van Booven D, Gannamedi DP, Stewart JB, Mok B, Liu DR, Lombard DB, Griswold AJ, Nedialkova DD, Moraes CT (2025) Correcting a pathogenic mitochondrial DNA mutation by base editing in mice. Science Translational Medicine 17: DOI: 10.1126/scitranslmed.adr0792.
The article “Jumping ‘Numts’ from Mitochondria Can Be Fast and Deadly” by Martin Picard, published online in Scientific American on January 3, 2025, sheds new light on a significant biological phenomenon with profound implications for both health and evolutionary biology.
Mitochondria have their own DNA, but over evolutionary time, they have transferred most of their genes to the host genome. Now research teams led by Martin Picard at Columbia University and Ryan Mills at the University of Michigan have found that this process is continuing to the present day, sometimes with profound implications for our health. 1, 2, 3
Mitochondrial DNA (mtDNA) fragments, known as nuclear mitochondrial DNA segments (numts), integrate into the nuclear genome at a surprisingly high rate, approximately once every 4,000 births.4 This process, called numtogenesis, does not just occur in the distant evolutionary past but continues actively throughout an individual’s life, particularly in brain cells where it might accelerate aging and reduce lifespan.
The significance of this finding lies in its potential to alter our understanding of genetic stability and disease, and of mitochondria themselves. By inserting into critical parts of our genome, Numts disrupt gene function,4 potentially leading to conditions, such as cancer or neurodegenerative diseases. The research also suggests that stress can amplify this DNA transfer, highlighting a new pathway through which environmental factors impact genetic health.
This discovery emphasizes the dynamic interplay between mitochondrial and nuclear genomes. It also reveals another way that mitochondria influence our lives: by changing the genome of our cells. Perhaps most importantly, it demonstrates the need for further investigation into how these interactions shape human health and longevity.
An interview with Martin Picard
- What made you begin your research into Numts?
We reviewed the literature on the many ways in which mitochondria influence gene expression and cellular behaviors. This highlighted a plurality of mechanisms.5 One of them is the transfer of mtDNA pieces to the nucleus, which could destabilize the genome, a hallmark of aging. This process is known to occur on the scale of millennia. So the initial thought was that this might be a mechanism of aging, just like the activation of “retrotransposons” that already live in our genomes cause aging.6 What if mitochondria—and particularly defective mitochondria in primary mitochondrial diseases or acquired mitochondrial defects—spit out pieces of DNA that disrupt the nucleus as a mechanism to speed up evolution but, in the process, end up driving the aging process? - How did you or others isolate this phenomenon?
We took a two-pronged approach. First, we used our Cellular Lifespan Study7 system where we can track the same cells over months in vitro, and we asked whether there were new Numts over this short time scale. The answer was a clear yes. It was particularly noted in cells that came from children with primary mitochondrial disorders, as predicted. Second, we had to check if this mattered to people: does it happen in the human body across a person’s lifetime? In blood, new Numts don’t accumulate. So we looked in the brains of about 1000 people who died of various causes. There, we found several new Numts that were “private” and unique to each person, meaning that there is almost no chance that they were inherited. So they must have arisen during a person’s lifetime. - If Numts are part of a larger process of the interaction between mtDNA and nuclear DNA, can you explain more about how the two genomes are designed how they interact with each other?
The mitochondria shipped pieces of their genome to the nuclear genome during evolution, explaining how it went from a full bacterial genome initially (with hundreds of genes) to only 37 now in our mitochondria. So as a result, the two genomes encode mitochondrial proteins and must be functionally coupled to make well-functioning, specialized mitochondria8 in each cell type. - Where do you see the research going from here, and how many labs, institutes or companies are working on these issues?
This study puts the process of Numt insertions, called Numtptogenesis, on the list of mechanisms of aging and possibly other diseases. In the brain, we found that people with more Numts in the prefrontal cortex, especially, died earlier than people with fewer new Numts. So maybe they regulate how long or how healthy we can live. There are many labs working on Numtogenesis as an evolutionary mechanism, and maybe our findings provide a rationale to studying this process in non-immune cells to understand its relevance to health. - Clearly, this is a frontier. What do you expect we will know more about in a year?
I hope we see researchers with whole-genome sequencing data on non-blood tissues explore and quantify the presence of Numts so we can see to what extent these results extend to other organs and health or disease phenotypes. For example, this may be relevant to mitochondrial diseases.
Comment by Alex Sercel
“The key advance of this work is measuring numtogenesis on a short timescale in tissue culture and in the somatic tissues of individuals over their lifespan instead of looking at the rate of Numt inheritance between generations. Genetic changes, such as Numts, are only observed in subsequent generations if they occur in the sperm or egg and are non-lethal to an individual’s progeny. Said differently, damaging numts are likely to be screened out by natural selection and are less likely to be seen in population-genetics studies.
“This work shows that Numts can occur more frequently than previously thought and may arise in all tissues of the body, specifically long-lived cells like neurons in the brain. The Numts that manifest in a person’s organs over the lifespan bear the potential to damage their cells and tissues because these genetic changes have not been subject to the selective pressures that filter out harmful mutations between generations,” Alex Sercel, PhD, MitoWorld’s Director of Scientific Affairs and a former Postdoctoral Scholar in the Picard Lab at Columbia University Irving Medical Center.
References
- Xue L, Moreira JD, Smith KK, Fetterman JL (2023) The Mighty NUMT: Mitochondrial DNA flexing its code in the nuclear genome. Biomolecules 13(5):753. doi: 3390/biom13050753
- Zhou W, Karan KR, Gu W, et al. (2024) Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts. PLoS Biol 22(8): e3002723.
https://doi.org/10.1371/journal.pbio.3002723 - Picard M (2025) Jumping ‘Numts’ from mitochondria can be fast and deadly. Scientific American.
https://www.scientificamerican.com/article/jumping-numts-from-mitochondria-can-be-fast-and-deadly/ - Wei W, Schon KR, Elgar G, et al.(2022) Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes. Nature 611: 105–114.
https://doi.org/10.1038/s41586-022-05288-7 - Picard M, Shirihai OS (2022) Mitochondrial signal transduction. Cell Metabolism 34: 1620–1653.
https://doi.org/10.1016/j.cmet.2022.10.008 - Gorbunova V, Seluanov A, Mita P et al.(2021) The role of retrotransposable elements in ageing and age-associated diseases. Nature 596: 43–53.
https://doi.org/10.1038/s41586-021-03542-y - Sturm G, Monzel AS, Karan KR, et al.(2022) A multi-omics longitudinal aging dataset in primary human fibroblasts with mitochondrial perturbations. Sci Data 9: 751.
https://doi.org/10.1038/s41597-022-01852-y - Monzel AS, Enríquez JA, Picard M (2023) Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction. Nat Metab5: 546–562.
https://doi.org/10.1038/s42255-023-00783-1
Mitochondria have long been recognized for the production of energy within cells. But there is more than one type of energy. In a recent review, Jacobs et al. (2024)1 described the results of their studies and that of others that show how mitochondria produce heat as well as chemical energy. Like many motors, mitochondria produce heat at the same time as performing ‘work’. Furthermore, they note that the heat produced by mitochondria might have been important in the evolution of eukaryotes and warm-blooded animals (e.g., birds, mammals).
Jacobs et al. used heat-sensitive dyes and fluorescent proteins to measure the temperature of mitochondria. They found that the temperature of the mitochondria was about 15°C higher than the environment.
They speculate that the heat energy had profound effects on life on Earth. First, eukaryotes resulted from an endosymbiotic relationship between a bacterium and another prokaryotic organism. The bacterium evolved into a mitochondrion. For some time, the assumption has been that the proto-mitochondrion provided additional chemical energy as ATP. However, Jacobs et al. point out that the most likely partner was an archaean that lived near a hydrothermal vent, as proposed originally by Dunn (2017)2. By entering into a partnership, the proto-mitochondrion provided heat that allowed the hybrid organism to move away from the warm waters of the hydrothermal vent. The most compelling aspect is that the transfer of heat does not require the evolution of additional mechanisms for transfer that ATP does. Second, the heat from mitochondria might have allowed warm-blooded animals to evolve.
While still just a hypothesis, the involvement of heat in evolution is an intriguing possibility that suggests lots of additional experiments.
1Jacobs HT, Rustin P, Bénit P, Davidi D, Terzioglu M (2024) Mitochondria: Great balls of fire. The FEBS Journal 291: 5327-5341. https://doi.org/10.1111/febs.17316
2Dunn CD (2017) Some liked it hot: A hypothesis regarding establishment of the proto-mitochondrial endosymbiont during eukaryogenesis. Journal of Molecular Evolution 85: 99-106. https://doi.org/10.1007/s00239-017-9809-5
We appreciate the willingness of lead author Howy Jacobs of Tampere University, Finland, to answer some questions about the significance of heat from mitochondria.For some time, biologists had assumed that energy was the main bartering chip provided by mitochondria to the new eukaryotes. Could heat be an equal driver, as Dunn suggests?
Well, heat IS a form of energy! What we are proposing is that heat produced by mitochondria (or by aerobic bacteria) is a crucial factor in eukaryote biology, that has been largely overlooked. We propose that it has a crucial role not only in evolution but also in many aspects of cell biology, metabolism, immunity, physiology and disease. Dunn’s idea is, of course, really only speculation at this point, but is now supported by the evidence that the ancient host cell that engulfed the mitochondrial ancestor was a moderate thermophile. Note also that it is not completely accurate to regard heat and ATP as alternative forms of energy produced by mitochondria: the energy conserved in the form of ATP and exported to the rest of the cell can also be converted partly or even entirely into heat. For example, the pumping action of the heart depends heavily on mitochondrial ATP production, but only a part of the stored energy drives the contractile action of the heart muscle, the rest being converted to heat which is then carried away in the bloodstream to maintain body temperature. Note that ATP may not be the only ‘energy-rich’ molecule produced by mitochondria that could be considered as a heat store.
Are you planning to measure the temperature of chloroplasts?
We are not planning to do this ourselves but at some point someone needs to do it. But it is going to require a different technology than the ones we have been using, which are based on fluorescent dyes and proteins. The green pigments naturally present in the photosynthetic system would just obliterate any signal. But the existing technologies should suffice to measure the intracellular temperature of aerobic bacteria and also to test our idea that the bacterial cell wall functions as an insulating layer.
Mitochondrial heating seems to open an entirely new way of looking at biology. There are so many manifestations that seem to be covered by it.
I am sure that the topics covered in our short review are far from exhaustive. Here are a few more than could be considered (but undoubtedly there are many others). We have suggested that ‘heat delivery’ could be a mechanism for killing pathogens or infected cells. But maybe it also plays a wider role in programmed cell death, which is a major process in animal and plant development, tumour suppression and stress management. Heat (or its absence) may also play a pivotal role in many diseases, notably neurodegeneration, where the accumulation of protein aggregates is an obligatory step in pathology. And if mitochondria do contain a store of heat-buffering molecules as suggested above, they might also function in some contexts to absorb excess heat coming from the environment.
What is the relationship between mitochondrial heating in brown adipose tissue and other tissues? Are there simply more mitochondria in brown adipose?
Although intensively studied, there are still outstanding questions as to how brown adipocyte mitochondria are ‘repurposed’ to deliver heat rather than ATP. One major mechanism is clearly the expression and activation of the uncoupler protein UCP1, which provides a proton channel in the inner mitochondrial membrane, thus dissipating the proton gradient that is normally driving ATP synthesis, instead releasing all the energy of substrate oxidation as heat. But the normal functioning of the respiratory chain in other tissues lacking UCP1 also generates heat, since only about half of the energy yield from biological oxidation is conserved by proton pumping against the gradient. The rest is converted to heat.
Do you have any speculation about the control systems for this heat?
Our FEBS Journal paper makes some suggestions as to the possible nature of heat sensors inside mitochondria (and the rest of the cell). But for now this is purely in the realm of speculation. The narrow temperature range tolerated by mammalian cells suggests that mitochondrial heat output must be finely regulated, almost certainly by multiple, i.e. redundant systems operating in parallel, as for almost all of the important processes in biology. Such redundancy invariably makes it hard to identify the relevant machinery using the standard tools of genetics.
Is it possible to determine the efficiency of mitochondria?
I don’t much care for this term, since it implies that heat production is somehow a wasteful by-product of mitochondrial metabolism. Thermodynamically it is appropriate, but biologically not! Rather I think we should be thinking about the overall energy transactions taking place, that result in the generation (or absorption) of heat, the production of heat- storage molecules (thus far not identified) and of ‘dual-use’ molecules, predominantly ATP, as a store of useful energy to drive biochemical, mechanical or electrical processes, as well as heat production. Yes, we can start to measure all these, and theoretical considerations can help, but to do this fully we need to identify all the cell’s heat storage systems and derive a more accurate picture of heat flow within the cell, including the temperature gradients within and between cellular compartments – not just mitochondria. Recent findings that mitochondria even within a single cell type can be functionally diverse further complicate the picture. So we are a long way from the end goal of comprehensively profiling energy transactions inside cells, let alone tissues and organs.
How did you get interested in mitochondria?
As so often in science, by studying something else and stumbling into mitochondria by accident. Details on request if you are really interested!
Navdeep “Nav” S. Chandel is both a leader and steward of the evolving field of mitochondrial biology.
As a newcomer to this area of science I was taken by Chandel’s energy, rigor, and enthusiasm for mitochondria, as well as his impatience on the pace of funding for the rapidly evolving field. Chandel provides leadership that is both expansive and contagious. It is a commitment that is necessary raise the visibility of the field across medicine, health, and research to stimulate more funding and to establish mitochondria as a unique field of science.
A Scientific American article in 1957 entitled “The Powerhouse of the Cell,” followed by three profound discoveries elucidating how mitochondria make energy – John Mitchell (Chemiosmotic hypothesis, Nobel 1978 ), Paul Boyer (ATP synthase, Nobel 1997 ) and John Walker (mechanisms of ATP synthase, Nobel 1997, shared with Boyer) sealed mitochondria’s identify as the converter of what we consume into the energy we use to power our cells, organs, and lives.
As a result, many biologists, researchers, textbook authors, and students failed to develop an understanding of mitochondria that went deeper than that. In many ways the science of mitochondria became limited to its role in energy production. For some time, this narrow view shut off further investigations. As a Ph.D. student in the 1990s at University of Chicago, Chandel began to suspect that mitochondria played many other significant roles. This became his passion when started his in his lab at Northwestern University in January 2000.
To understand Chandel’s contribution to the field, just ask his colleagues.
“The work of Navdeep’s lab, and especially his intellectual leadership, has been transformational for the field,” says Gerry Shadel, of the Salk Institute. “Navdeep has been at the forefront for decades of trying to convince the world to think about mitochondria beyond just making ATP. This position has turned out to be prescient as we have learned of the many, many ways that mitochondria impact health and disease, many of which have little to do with producing ATP.”
Chandel’s work in recognizing mitochondrial functions beyond ATP production has been part of the process to reinterpret mitochondria much more broadly.
“For decades, the mitochondria have been primarily viewed as biosynthetic and bioenergetic organelles generating metabolites for the production of macromolecules and ATP, respectively. We began to provide initial evidence that mitochondria have a third distinct role whereby they participate in cellular signaling processes to control physiology through the release of reactive oxygen species (ROS), “Chandel wrote on his website. “In the past two decades, many scientists have contributed to elucidating multiple modalities of how mitochondria communicate with the rest of the cell to dictate their function in physiological contexts. A key aspect of mitochondrial signaling paradigm is that various pathologies linked to mitochondria dysfunction might occur not simply due to lack of ATP generation or metabolites but disruption of these normal signaling functions of mitochondria”.
This expanded view reflects what Chandel has been able to accomplish by showing that mitochondria are not a biological sideshow, but a star that belongs on the main stage.
“Navdeep has made numerous profound contributions to the understanding of how mitochondrial function and disruption contributes to human pathology, particularly in cancer and immunology,” said Mike Murphy, program leader at the University of Cambridge’s MRC Mitochondrial Biology Unit. “Navdeep has pioneered the use of innovative transgenic animal models in which subtle modulation of respiratory function leads to important new insights into disease processes and opens the way to the development of novel therapies.”
Allyson Evans, editor in chief of the journal Cell Metabolism, in 2013 established a new symposium, the “Multifaceted Mitochondria Symposium.” The conference is held every two years. I just attended the 2024 Symposium in Sitges, Spain, where MitoWorld was a sponsor. Before I did, I had an opportunity to ask Evans how she and Cell decided to launch a symposium dedicated to mitochondria a decade ago, and how they gave it the name, “Multi-Faceted Mitochondria.” Her answer was simple. It was Navdeep Chandel who stimulated the interest and advocated for it.
This was same for our launching the global web portal MitoWorld, www.MitoWorld.org, in 2023. Chandel provided the confidence and connections for MitoWorld to begin its mission to mainstream mitochondria issues, provide a community hub for the public, patient, and professional mitochondria communities; and to advocate for the development of a mitochondrial science and informatics.
For others to get to know Chandel better, we asked life sciences journalist Daniel Levine to interview Navdeep for MitoWorld’s “Spotlight” section of the MitoWorld website.
About Navdeep S. Chandel, PhD:
Navdeep S. Chandel, PhD is the David W. Cugell Professor of Medicine, Biochemistry, and Molecular Genetics at Northwestern University. He received his BA in Mathematics (1991) and Ph.D. in Cell Physiology at the University of Chicago (1993-1997, Paul Schumacker) as well as a post-doctoral fellowship at the University of Chicago (1997-1999, jointly with Paul Schumacker and Craig Thompson). In 2000, he started his laboratory at Northwestern University on the concept of “Mitochondria as signaling organelles”. He has written a widely utilized introductory book entitled “Navigating Metabolism” (Cold Spring Harbor Press, 2014). He received the Clarence Ver Steeg Faculty Mentor Award in 2013, which recognizes faculty members from any department throughout Northwestern University for their outstanding mentorship of graduate students. In 2023, he was co-recipient of the FNIH Lurie Prize in Biomedical Science with Dr. Vamsi Mootha.
We were honored to hold an interactive session on the work of www.mitoworld.org at the CELL: Multifaceted Mitochondria Symposium in Sitges, Spain, October 27-29.
Three members of the MitoWorld scientific advisory board (Gerry Shadel, Salk Institute for Biological Studies, Mike Murphy, University of Cambridge Mitochondrial Biology Unit, and Heidi McBride, McGill University and I spoke about MitoWorld’s efforts to “mainstream” mitochondria for the public and to the medical sector, pushing also toward a more encompassing mitochondrial science, and beginning a mitochondrial informatics effort.
As a new organization, we were able to hear from the attendees on what they felt was necessary to help the mitochondrial field get more attention and to communicate how essential mitochondria are to health, disease mitigation and solving complex issues from childhood mitochondrial mutation diseases to the issues of aging and age-related diseases, many of which are without therapies.
Symposium attendance was over four hundred mitochondrial researchers from around the world with strong representation from the U.S., UK, Australia, China, Korea, Finland, Germany, Spain and Italy among others. It was also a powerful venue for the interaction between senior researchers and postdocs coming into their positions into the field which is now growing.
Attendees shared with our panel that the public and professional dialog needs to be widened globally. There was an interest in participation with MitoWorld from many of the labs.
The panel invited comments on MitoWorld’s interest in building task forces in various arenas of mitochondrial research mapped to medical practice areas and well-known research subjects. While the task forces idea was well received, the most interest was in finding ways to educate or inform doctors and the medical profession about mitochondria in specific practice areas.
In this case, mitochondria are like the hidden hand in physiology that is not often considered in diagnoses or treatment.
Additionally, there was a sense that the subject of mitochondrial research and eventual practice has to be seen as “across the lifespan,” that mitochondria are ubiquitous and consequential at every stage while, at present, the practice areas are the mutation diseases of early life and the complications of mitochondrial decline in the diseases of aging.
The subject of education, starting in school and college and in medical training, came up several times as a way to anchor mitochondria in culture and eventually in practice. It should be noted that MitoWorld is a project of the R & D nonprofit National Laboratory for Education Transformation, www.NLET.org in California.
We hope the momentum from the Symposium will help build MitoWorld globally.
Professor at University College London was recognized for his work connecting mitochondria to human diseases and for finding potential therapeutic targets.
MitoWorld congratulates Professor Michael Duchen on being awarded the prestigious 2024 Keilin Memorial Lecture by the Biochemical Society. Each year, the Society recognizes outstanding scientists for achievements in the study of molecular biosciences. Professor Duchen was honored for his seminal contributions to the research into mitochondria in disease.
“This award is a great honor, and I thank the Biochemical Society for it,” said Professor Duchen. “I accepted the Keilin award on behalf of the lab. I have been very lucky to work with outstanding people over the years who shaped the work that we have generated. I am not the one who is coming to work at weekends to feed the iPS cells or working late at night because that’s the only time the confocal microscope is free! Many of those people are now professors and some of the greatest pleasure comes from seeing people grow and flower and find their own scientific voice.”
Working at University College London since 1981, Duchen began his research into neurotransmitter receptors and then calcium signaling and metabolism and finally mitochondria. He has been a leader in connecting mitochondrial dysfunction to diseases and in establishing mitochondria as therapeutic targets for a variety of diseases.
MitoWorld reached out to Professor Duchen to learn more about his research. His responses to our questions are reproduced here.
How did your research evolve from signaling and metabolism to mitochondria?
The story is a bit long? My PhD supervisor, Tim Biscoe, had previously done some work on the carotid body, the structure that sits on the carotid artery and senses and reports oxygen tension in the arterial blood en route to the brain. We were using patch clamp techniques to study neurotransmitter receptors in freshly dissociated neurons and one day had a visit from an old friend of Tim’s, Jose Ponte, who suggested we try to patch cells isolated from the carotid body. We tried as a ‘Friday afternoon experiment’. No one knew anything at all about the physiology of these cells, and we discovered that they were excitable. The question then was how do they respond to low oxygen? There was some evidence from Elliott Mills that mitochondria might be involved as mitochondria are the main oxygen consumers. That made sense. I was then faced with the challenge of how to study changes in mitochondrial function in these cells in response to changing pO2, especially difficult as the structure is very tiny with a very small population of cells. That eventually led to measurements of changing mitochondrial membrane potential in response to graded changes in oxygen which were amongst the first measurements of changing mitochondrial membrane potential in living cells. That opened up a huge swathe of questions about how mitochondria behave in different cell types and in response to different physiological conditions or in disease, about which we then knew nothing at all, and those questions have kept me busy for ~30 years!
What are the main connections between mitochondria and diseases, such as PD?
We can broadly divide roles of mitochondrial dysfunction in disease into ‘primary’ where the primary defect is in the mitochondria, such as a mutation of mitochondrial DNA (mtDNA) and ‘secondary’, where mitochondria are damaged as part of a cascade of cell injury and the defect is extramitochondrial. The latter group probably includes diseases, such as Parkinson’s disease (PD), amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer’s disease and many others. It seems clear at least in familial forms of PD, that the primary genetic defects lie on pathways that have an impact on mitochondrial function. As the resulting mitochondrial dysfunction may play a critical role in defining the disease progression, this is still an interesting potential therapeutic target.
What potential therapeutic targets interest you most?
Recent work has highlighted multiple pathways that affect and are affected by mitochondrial function in a host of different ways. These include cell death pathways governed by mitochondria, mitochondrial quality control pathways that include biogenesis, mitophagy, fission, fusion and trafficking, and most recently the activation of innate immune pathways by mtDNA that is released from damaged mitochondria. All of these pathways represent potential therapeutic targets.
Is any disease “low hanging fruit” for mitochondrial treatments?
There may be low hanging fruit in relation to process rather than to one specific disease. There is quite a lot of evidence for a mitochondrial catastrophe. The opening of the mitochondrial permeability transition pore may be the cause of sudden cell death of cell dysfunction in multiple diseases. This is most interesting as the pore is an established therapeutic target, but so far, preclinical findings haven’t translated well into the clinic. I like to think that, if we could find a compound without unwanted off target effects and with good pharmacokinetic properties, this might prove valuable in multiple diseases. Mitophagy and biogenesis also appear to be a potentially powerful processes that can be modulated pharmacologically, and I suspect those will prove to be major drug targets in multiple human diseases.
For more information on Professor Duchen, please visit his UCL website at https://profiles.ucl.ac.uk/3559. More information on the Biochemical Society awards can be found at www.biochemistry.org/about-us/news-media/biochemical-society-announces-2024-award-recipients/.