A person can carry a pathogenic mitochondrial DNA mutation and remain clinically well for years, while another person with the same variant develops severe neurological, muscular, cardiac, sensory, or metabolic disease. Even within the same family, age of onset, affected organs, and disease severity can differ markedly. One population study estimated that at least 1 in 200 healthy people carries a pathogenic mtDNA mutation, while a separate study in northeast England found clinically manifest mitochondrial disease in approximately 1 in 8,000 adults. A pathogenic mitochondrial mutation can therefore exist in a very different biological setting from one tissue, or one person, to another.
Much of that uncertainty comes from the unusual genetics of mitochondria. Most cells with mitochondria contain many copies of mitochondrial DNA (mtDNA), and normal and mutant genomes can coexist in a state known as heteroplasmy. The proportion of mutant mtDNA is not necessarily the same in muscle, brain, blood, heart, or other tissues, and disease can emerge when the mutant burden in a particular tissue exceeds the amount of dysfunction that tissue can tolerate. High-demand tissues often have less room to absorb that loss of mitochondrial capacity, which helps explain why the brain, skeletal muscle, heart, retina, optic nerve, and peripheral nervous system feature so prominently in mitochondrial disease.
The result is a group of diseases that can look very different from one person to the next. Mitochondrial disorders may appear in infancy, childhood, or adulthood and can produce combinations of developmental regression, seizures, stroke-like episodes, muscle weakness, exercise intolerance, ptosis, cardiomyopathy, hearing loss, vision loss, neuropathy, diabetes, gastrointestinal dysfunction, and other manifestations depending on the mutation and tissues involved. A diagnosis such as MELAS, Leigh syndrome, Leber hereditary optic neuropathy, or mitochondrial myopathy describes one recognizable pattern within a much larger spectrum of disorders produced by failures in mitochondrial function.
Underneath that clinical variety is a common physiological pressure: cells still have to meet their energy requirements when oxidative phosphorylation is compromised. Electrons normally move through respiratory-chain complexes in the inner mitochondrial membrane, building the proton gradient that ultimately drives ATP synthesis. Mutations affecting that machinery can disturb electron transfer, reduce bioenergetic capacity, alter mitochondrial membrane potential and redox balance, increase reactive oxygen species (ROS), disrupt calcium signaling, and shift cellular metabolism as cells attempt to compensate for impaired oxidative phosphorylation. In mitochondrial myopathy, impaired electron transport can increase cytosolic NADH and favor conversion of pyruvate to lactate, which is one reason lactate and the lactate-to-pyruvate ratio have been used as biochemical indicators of mitochondrial respiratory dysfunction.
A mitochondrial mutation may remain for life, but the mitochondrial population around it is constantly changing. Mitochondria continually divide and fuse, damaged organelles can be selectively removed through mitophagy, and mitochondrial biogenesis can expand or renew the mitochondrial population. Cells also respond to disturbances in mitochondrial protein balance through stress programs that alter gene expression and protein quality control, including the mitochondrial unfolded protein response (UPRmt). Together, mitophagy, biogenesis, fusion and fission, and mitochondrial proteostasis determine how effectively a cell maintains the mitochondrial network when some of its components are damaged or inefficient. These systems matter particularly in genetic mitochondrial disease because the underlying mutation may remain present while the cell continually adjusts which mitochondria are maintained, which are removed, and how much functional mitochondrial capacity can be preserved around the defect.
Molecular hydrogen (H₂) has begun to intersect with this biology surprisingly close to the respiratory chain itself. More than a decade ago, researchers tested hydrogen-enriched water in people with mitochondrial myopathies, including patients with MELAS and chronic progressive external ophthalmoplegia. The initial open-label study found a reduction in the lactate-to-pyruvate ratio among five participants with mitochondrial myopathy, and a subsequent randomized, double-blind, placebo-controlled crossover trial involving 12 patients found a significant reduction in serum lactate during hydrogen-water treatment. Neither trial demonstrated objective improvement in clinical symptoms, leaving a biochemical signal without evidence that the patients' disease or physical function had meaningfully improved.
At the time, the mitochondrial effects of H₂ were still discussed largely through oxidative stress and incompletely defined signaling mechanisms. Subsequent experiments have moved the interaction closer to the machinery responsible for electron transport. In isolated mitochondria and cultured cells, H₂ altered mitochondrial electron flow, suppressed superoxide generation associated predominantly with Complex I, and modestly reduced mitochondrial membrane potential. Separate animal experiments found that H₂ induced genes associated with the UPRmt, linking hydrogen exposure with a mitochondrial stress-response program rather than only with direct neutralization of reactive molecules.
Then, in 2025, researchers identified a potential mitochondrial target that connected those observations. H₂ rapidly suppressed the activity of respiratory-chain Complex III and promoted LONP1-dependent degradation of the Rieske iron-sulfur protein (RISP), an essential Complex III component. Loss of RISP was followed by activation of the UPRmt and subsequent changes in mitochondrial electron-transport activity. Rather than protecting mitochondria by leaving their activity undisturbed, H₂ produced a transient mitochondrial perturbation that was followed by an adaptive stress response, a pattern consistent with the broader concept of mitochondrial hormesis, or mitohormesis, in which a limited mitochondrial stress can activate responses that improve the cell's ability to manage subsequent stress.
The next question is what happens to mitochondria that have already become dysfunctional. Here, H₂ research has repeatedly converged on mitophagy. In cells and mice exposed to severe inflammatory stress, H₂ enhanced PINK1/Parkin-mediated mitophagy. When researchers knocked down PINK1, both the increase in mitophagy and much of H₂'s protection against cellular injury were lost. A separate mouse study approached the same question through FUNDC1, another regulator of mitophagy. Hydrogen inhalation improved mitochondrial respiratory control and reduced septic liver injury, but blocking FUNDC1 eliminated the difference between hydrogen-treated and untreated animals, providing stronger evidence that mitochondrial clearance contributed functionally to the response.
Removing dysfunctional mitochondria solves only half of the quality-control problem; cells also need to maintain or rebuild mitochondrial capacity. In mice with sepsis-associated brain injury, H₂ increased mitochondrial membrane potential, ATP levels, Complex I activity, and expression of PGC-1α, NRF2, and TFAM, a group of regulators involved in mitochondrial biogenesis. Inhibiting PGC-1α weakened both the mitochondrial changes and the protective response, placing biogenesis within the mechanism rather than merely alongside it.
There is also evidence that H₂ can influence the physical remodeling of the mitochondrial network. In septic mice, hydrogen inhalation increased ATP, mitochondrial membrane potential, respiratory control, Complex I activity, and expression of the fusion protein MFN2 while reducing the fission-associated protein Drp1. In cultured human endothelial cells exposed to inflammatory stress, hydrogen-rich medium similarly reduced excessive Drp1-associated mitochondrial fission while improving ATP content, membrane potential, and maximal respiration. Inhibiting HO-1 abolished those effects. These are disease models rather than models of inherited mitochondrial disease, but they show that H₂ can interact with several components of the machinery cells use to preserve a functioning mitochondrial population.
An exercise experiment adds an interesting wrinkle to the hormesis argument. High doses of conventional antioxidants can sometimes suppress ROS-dependent signals that participate in training adaptation. In rats exercising on a treadmill, vitamin C reduced several post-exercise signals associated with mitochondrial biogenesis, whereas hydrogen inhalation reduced oxidative-stress markers without producing the same suppression of PGC-1α, TFAM, and related mitochondrial signals. The experiment does not establish that H₂ preserves mitochondrial adaptation in people with mitochondrial disease, but it supports the possibility that modifying excessive oxidative pressure does not necessarily require eliminating the signaling needed for mitochondrial remodeling.
Human evidence outside primary mitochondrial disease provides another useful bridge. In a placebo-controlled study of 30 people with non-alcoholic fatty liver disease (NAFLD), eight weeks of hydrogen-rich water increased platelet coenzyme Q10, reduced an oxidative-stress marker, and improved the efficiency of mitochondrial oxidative phosphorylation measured by high-resolution respirometry. Although platelets are not skeletal muscle, brain, or heart, and NAFLD is not a primary mitochondrial disorder, the study is important because it moves the mitochondrial argument from animal tissues and cultured cells into directly measured human bioenergetics. It also links improved OXPHOS efficiency with an increase in CoQ10, the mobile electron carrier that transfers electrons from Complexes I and II to Complex III.
Animal work points in the same direction. In rats, hydrogen-rich water increased cardiac mitochondrial respiratory-chain activity, ATP production supported by Complex I and Complex II, and mitochondrial coenzyme Q9. Together, the human and animal findings suggest that H₂ can influence the CoQ system and mitochondrial bioenergetics. Viewed alongside its effects on Complex I and Complex III, the pattern suggests that H₂ may first alter electron transport and later support adaptive changes in mitochondrial function, although that sequence has not yet been demonstrated directly in humans.
That sequence gives mitochondrial disease research a more complicated question to pursue. The pathogenic mutation remains unchanged, and the single controlled human study conducted so far did not show objective clinical improvement. But the experimental H₂ literature now reaches into many of the systems cells use to manage mitochondrial dysfunction: electron handling at Complexes I and III, UPRmt signaling, mitophagy, mitochondrial biogenesis, fusion and fission, and, increasingly, CoQ-related bioenergetics. Human research has also begun to show measurable changes in mitochondrial function, although not yet clinical benefit in primary mitochondrial disease.
That distinction should remain clear. H₂ does not remove a pathogenic mtDNA mutation, correct a defective nuclear gene, or replace a missing respiratory-chain protein. Its potential relevance lies further downstream in how cells respond to impaired electron transport, metabolic stress, damaged mitochondria, and declining mitochondrial efficiency. Whether that translates into better exercise tolerance, less fatigue, preserved muscle function, improved neurological performance, fewer metabolic disturbances, or slower functional decline remains unknown.
Future studies will need to determine whether those mitochondrial effects produce changes that patients can actually feel or use. Exercise capacity, muscle strength, fatigue, neurological function, daily activity, and quality of life will ultimately matter more than a change in lactate alone, although metabolic and mitochondrial measurements will remain important for understanding why a response occurs. Differences in genotype, heteroplasmy, and tissue involvement may also prove important in determining who responds.
For now, H₂ belongs in the experimental-adjunct category rather than the disease-modifying one. Its scientific interest lies in the gap between the genetic defect and the functional consequences that follow from it. A pathogenic mutation may remain fixed, but mitochondria are continually being removed, rebuilt, reshaped, and metabolically adjusted around that defect. If H₂ ultimately proves useful in mitochondrial disease, its value may lie in influencing that adaptive machinery, helping cells preserve more usable mitochondrial function without pretending to erase the mutation that caused the problem in the first place.
References
· Chaoqun, L., Yuqi, Z., Shi, Z., Zhenghui, Y., & Li, W. (2021). A Comparison of the Antioxidant Effects Between Hydrogen Gas Inhalation and Vitamin C Supplementation in Response to a 60-Min Treadmill Exercise in Rat Gastrocnemius Muscle. Frontiers in physiology, 12, 745194. https://doi.org/10.3389/fphys.2021.745194
· Chen, H., Lin, H., Dong, B., Wang, Y., Yu, Y., & Xie, K. (2021). Hydrogen alleviates cell damage and acute lung injury in sepsis via PINK1/Parkin-mediated mitophagy. Inflammation research : official journal of the European Histamine Research Society ... [et al.], 70(8), 915–930. https://doi.org/10.1007/s00011-021-01481-y
· Dong, A., Yu, Y., Wang, Y., Li, C., Chen, H., Bian, Y., Zhang, P., Zhao, Y., Yu, Y., & Xie, K. (2018). Protective effects of hydrogen gas against sepsis-induced acute lung injury via regulation of mitochondrial function and dynamics. International immunopharmacology, 65, 366–372. https://doi.org/10.1016/j.intimp.2018.10.012
· Elliott, H. R., Samuels, D. C., Eden, J. A., Relton, C. L., & Chinnery, P. F. (2008). Pathogenic mitochondrial DNA mutations are common in the general population. American journal of human genetics, 83(2), 254–260. https://doi.org/10.1016/j.ajhg.2008.07.004
· Gorman, G. S., Chinnery, P. F., DiMauro, S., Hirano, M., Koga, Y., McFarland, R., Suomalainen, A., Thorburn, D. R., Zeviani, M., & Turnbull, D. M. (2016). Mitochondrial diseases. Nature reviews. Disease primers, 2, 16080. https://doi.org/10.1038/nrdp.2016.80
· Gorman, G. S., Schaefer, A. M., Ng, Y., Gomez, N., Blakely, E. L., Alston, C. L., Feeney, C., Horvath, R., Yu-Wai-Man, P., Chinnery, P. F., Taylor, R. W., Turnbull, D. M., & McFarland, R. (2015). Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Annals of neurology, 77(5), 753–759. https://doi.org/10.1002/ana.24362
· Gvozdjáková, A., Kucharská, J., Kura, B., Vančová, O., Rausová, Z., Sumbalová, Z., Uličná, O., & Slezák, J. (2020). A new insight into the molecular hydrogen effect on coenzyme Q and mitochondrial function of rats. Canadian journal of physiology and pharmacology, 98(1), 29–34. https://doi.org/10.1139/cjpp-2019-0281
· Ishihara, G., Kawamoto, K., Komori, N., & Ishibashi, T. (2020). Molecular hydrogen suppresses superoxide generation in the mitochondrial complex I and reduced mitochondrial membrane potential. Biochemical and biophysical research communications, 522(4), 965–970. https://doi.org/10.1016/j.bbrc.2019.11.135
· Ito, M., Ibi, T., Sahashi, K., Ichihara, M., Ito, M., & Ohno, K. (2011). Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies. Medical gas research, 1(1), 24. https://doi.org/10.1186/2045-9912-1-24
· Lian, N., Mao, X., Su, Y., Wang, Y., Wang, Y., Wang, Y., Chen, H., Zhu, R., Yu, Y., & Xie, K. (2022). Hydrogen-rich medium ameliorates lipopolysaccharides-induced mitochondrial fission and dysfunction in human umbilical vein endothelial cells (HUVECs) via up-regulating HO-1 expression. International immunopharmacology, 110, 108936. https://doi.org/10.1016/j.intimp.2022.108936
· Mei, J., Ding, P., Gao, C., Zhou, J., Li, Z., Zhang, C., & Gao, J. (2025). Mitochondrial Diseases: Molecular Pathogenesis and Therapeutic Advances. MedComm, 6(9), e70385. https://doi.org/10.1002/mco2.70385
· Negishi, S., Ito, M., Hasegawa, T., Otake, H., Ohkawara, B., Masuda, A., Mino, H., LeBaron, T. W., & Ohno, K. (2025). The Rieske iron-sulfur protein is a primary target of molecular hydrogen. Redox biology, 88, 103952. https://doi.org/10.1016/j.redox.2025.103952
· Paulsen, G., Cumming, K. T., Holden, G., Hallén, J., Rønnestad, B. R., Sveen, O., Skaug, A., Paur, I., Bastani, N. E., Østgaard, H. N., Buer, C., Midttun, M., Freuchen, F., Wiig, H., Ulseth, E. T., Garthe, I., Blomhoff, R., Benestad, H. B., & Raastad, T. (2014). Vitamin C and E supplementation hampers cellular adaptation to endurance training in humans: a double-blind, randomised, controlled trial. The Journal of physiology, 592(8), 1887–1901. https://doi.org/10.1113/jphysiol.2013.267419
· Picca, A., Faitg, J., Auwerx, J., Ferrucci, L., & D'Amico, D. (2023). Mitophagy in human health, ageing and disease. Nature metabolism, 5(12), 2047–2061. https://doi.org/10.1038/s42255-023-00930-8
· Refrigeri, M., Tola, A., Mogavero, R., Pietracupa, M. M., Gionta, G., & Scatena, R. (2026). Mitochondrial myopathy biomarkers. Advances in clinical chemistry, 133, 161–216. https://doi.org/10.1016/bs.acc.2026.01.007
· Sano, M., & Fukuda, K. (2008). Activation of mitochondrial biogenesis by hormesis. Circulation research, 103(11), 1191–1193. https://doi.org/10.1161/CIRCRESAHA.108.189092
· Sobue, S., Inoue, C., Hori, F., Qiao, S., Murate, T., & Ichihara, M. (2017). Molecular hydrogen modulates gene expression via histone modification and induces the mitochondrial unfolded protein response. Biochemical and biophysical research communications, 493(1), 318–324. https://doi.org/10.1016/j.bbrc.2017.09.024
· Sumbalová, Z., Kucharská, J., Rausová, Z., Gvozdjáková, A., Szántová, M., Kura, B., Mojto, V., & Slezák, J. (2023). The Effect of Adjuvant Therapy with Molecular Hydrogen on Endogenous Coenzyme Q10 Levels and Platelet Mitochondrial Bioenergetics in Patients with Non-Alcoholic Fatty Liver Disease. International journal of molecular sciences, 24(15), 12477. https://doi.org/10.3390/ijms241512477
· Xie, K., Wang, Y., Yin, L., Wang, Y., Chen, H., Mao, X., & Wang, G. (2025). Hydrogen Gas Alleviates Sepsis-Induced Brain Injury by Improving Mitochondrial Biogenesis Through the Activation of PGC-α in Mice: Erratum. Shock (Augusta, Ga.), 64(6), 571–572. https://doi.org/10.1097/SHK.0000000000002779
· Yan, M., Yu, Y., Mao, X., Feng, J., Wang, Y., Chen, H., Xie, K., & Yu, Y. (2019). Hydrogen gas inhalation attenuates sepsis-induced liver injury in a FUNDC1-dependent manner. International immunopharmacology, 71, 61–67. https://doi.org/10.1016/j.intimp.2019.03.021
· Zhu, L., Zhou, Q., He, L., & Chen, L. (2021). Mitochondrial unfolded protein response: An emerging pathway in human diseases. Free radical biology & medicine, 163, 125–134. https://doi.org/10.1016/j.freeradbiomed.2020.12.013