Mitochondrial Dysfunction as a Convergent Mechanism in Spaceflight-Associated Pathology: Implications for Countermeasure Development
DOI:
https://doi.org/10.65166/ty692t56Keywords:
spaceflight, microgravity, space radiation, mitochondrial dysfunction, oxidative stress, biomedical countermeasuresAbstract
Long-duration human spaceflight exposes crews to chronic microgravity and elevated space radiation, producing interacting cellular stresses that affect multiple organ systems. This thematic analytical review examines mitochondrial dysfunction as a convergent mechanism linking these environmental stressors to spaceflight-associated pathology and evaluates the potential of mitochondrial-targeted countermeasures. Evidence from human and animal spaceflight missions, ground-based analogs, and mechanistic studies was synthesized across five areas: microgravity and radiation exposure, mitochondrial homeostasis, pathways of mitochondrial impairment, organ-specific manifestations, and emerging countermeasures. The reviewed evidence indicates that spaceflight conditions can suppress mitochondrial biogenesis, impair electron transport chain activity, increase reactive oxygen species production, damage mitochondrial DNA, and disrupt mitochondrial dynamics and quality-control processes. The causal evidence is strongest for skeletal muscle atrophy, where mitochondrial impairment appears to interact bidirectionally with unloading and proteolytic pathways. In neurological, ocular, and cardiovascular outcomes, mitochondrial dysfunction is consistently observed but remains one of several interacting mechanisms. Mitochondrial-targeted antioxidants, NAD+ precursors, and mitophagy-modulating agents demonstrate potential in terrestrial and ground-based models, although direct validation under actual spaceflight conditions remains limited. The findings support treating mitochondrial protection as a complementary strategic component of space biomedical countermeasure development. Priorities include in-space intervention studies, validated mitochondrial biomarkers, long-duration safety evaluation, combination-countermeasure testing, and assessment of individual susceptibility.
Downloads
References
Alaghband, Y., Klein, P., Kramár, E. A., Cranston, M. N., Perry, B. C., Shelerud, L., Kane, A. E., Doan, N.-L., Ru, N., Acharya, M. M., Wood, M. A., Sinclair, D., Dickstein, D. L., Soltész, I., Limoli, C. L., & Baulch, J. E. (2023). Galactic cosmic radiation exposure causes multifaceted neurocognitive impairments. Cellular and Molecular Life Sciences, 80, Article 29. https://doi.org/10.1007/s00018-022-04666-8
Baran, R., Marchal, S., Garcia Campos, S., Rehnberg, E., Tabury, K., Baselet, B., Wehland, M., Grimm, D., & Baatout, S. (2022). The cardiovascular system in space: Focus on in vivo and in vitro studies. Biomedicines, 10(1), Article 59. https://doi.org/10.3390/biomedicines10010059
Bateman, G. A., & Bateman, A. R. (2024). A perspective on the evidence for glymphatic obstruction in spaceflight associated neuro-ocular syndrome and fatigue. npj Microgravity, 10, Article 23. https://doi.org/10.1038/s41526-024-00365-9
Chen, X., Ji, Y., Liu, R., Zhu, X., Wang, K., Yang, X., Liu, B., Gao, Z., Huang, Y., Shen, Y., Liu, H., & Sun, H. (2023). Mitochondrial dysfunction: Roles in skeletal muscle atrophy. Journal of Translational Medicine, 21, Article 503. https://doi.org/10.1186/s12967-023-04369-z
Cialdai, F., Brown, A., Baumann, C. W., Angeloni, D., Baatout, S., Benchoua, A., Bereiter-Hahn, J., Bottai, D., Buchheim, J., Calvaruso, M., Carnero-Díaz, E., Castiglioni, S., Cavalieri, D., Ceccarelli, G., Choukér, A., Ciofani, G., Coppola, G., De Angelis, M. G. C., Degl’Innocenti, A., . . . Monici, M. (2023). How do gravity alterations affect animal and human systems at a cellular/tissue level? npj Microgravity, 9, Article 84. https://doi.org/10.1038/s41526-023-00330-y
Faitg, J., D’Amico, D., Rinsch, C., & Singh, A. (2024). Mitophagy activation by urolithin A to target muscle aging. Calcified Tissue International, 114(1), 53-59. https://doi.org/10.1007/s00223-023-01145-5
Guaragnella, N., Di Noia, M. A., & Primavera, A. (2024). Mitochondrial (dys)function: A double edge sword in cell stress response. Frontiers in Cell Death, 3, Article 1467272. https://doi.org/10.3389/fceld.2024.1467272
Han, X., Qu, L., Yu, M., Ye, L., Shi, L., Ye, G., Yang, J., Wang, Y., Fan, H., Wang, Y., Tan, Y., Wang, C., Li, Q., Lei, W., Chen, J., Liu, Z., Shen, Z., Li, Y., & Hu, S. (2024). Thiamine-modified metabolic reprogramming of human pluripotent stem cell-derived cardiomyocyte under space microgravity. Signal Transduction and Targeted Therapy, 9, Article 86. https://doi.org/10.1038/s41392-024-01791-7
Juhl, O. J., Buettmann, E. G., Friedman, M., DeNapoli, R. C., Hoppock, G. A., & Donahue, H. J. (2021). Update on the effects of microgravity on the musculoskeletal system. npj Microgravity, 7, Article 28. https://doi.org/10.1038/s41526-021-00158-4
Kıran, T. R., Otlu, Ö., & Karabulut, A. B. (2023). Oxidative stress and antioxidants in health and disease. Journal of Laboratory Medicine, 47(1), 1-11. https://doi.org/10.1515/labmed-2022-0108
Lei, Y., Gan, M., Qiu, Y., Chen, Q., Wang, X., Liao, T., Zhao, M., Chen, L., Zhang, S., Zhao, Y., Niu, L., Wang, Y., Zhu, L., & Shen, L. (2024). The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: From molecular mechanisms to therapeutic insights. Cellular & Molecular Biology Letters, 29, Article 59. https://doi.org/10.1186/s11658-024-00572-y
Liu, B., Xu, C.-Z., Liu, Y., Lu, Z., Fu, T.-L., Li, G., Deng, Y., Luo, G., Ding, S., Li, N., & Geng, Q. (2024). Mitochondrial quality control in human health and disease. Military Medical Research, 11, Article 32. https://doi.org/10.1186/s40779-024-00536-5
Lü, Y., Li, Z., Zhang, S., Zhang, T., Liu, Y., & Zhang, L. (2023). Cellular mitophagy: Mechanism, roles in diseases and small molecule pharmacological regulation. Theranostics, 13(2), 736-766. https://doi.org/10.7150/thno.79876
Mair, D. B., Tsui, J. H., Higashi, T., Koenig, P., Dong, Z., Chen, J. F., Meir, J. U., Smith, A. S. T., Lee, P. H. U., Countryman, S., Sniadecki, N. J., & Kim, D. (2024). Spaceflight-induced contractile and mitochondrial dysfunction in an automated heart-on-a-chip platform. Proceedings of the National Academy of Sciences of the United States of America, 121(40), Article e2404644121. https://doi.org/10.1073/pnas.2404644121
Masarapu, Y., Cekanaviciute, E., Andrusivová, Ž., Westholm, J. O., Björklund, Å. K., Fallegger, R., Badia-i-Mompel, P., Boyko, V., Vasisht, S., Saravia-Butler, A., Gebre, S., Lázár, E., Graziano, M., Frapard, S., Hinshaw, R. G., Bergmann, O., Taylor, D. M., Wallace, D. C., Sylvén, C., . . . Giacomello, S. (2024). Spatially resolved multiomics on the neuronal effects induced by spaceflight in mice. Nature Communications, 15, Article 4778. https://doi.org/10.1038/s41467-024-48916-8
Memme, J. M., & Hood, D. A. (2021). Molecular basis for the therapeutic effects of exercise on mitochondrial defects. Frontiers in Physiology, 11, Article 615038. https://doi.org/10.3389/fphys.2020.615038
Moosavi, D., Wolovsky, D., Depompeis, A., Uher, D., Lennington, D., Bodden, R., & Garber, C. E. (2021). The effects of spaceflight microgravity on the musculoskeletal system of humans and animals, with an emphasis on exercise as a countermeasure: A systematic scoping review. Physiological Research, 70(2), 119-151. https://doi.org/10.33549/physiolres.934550
Mu, Y., Wei, D., Yao, L., Xu, X., Li, S., Cao, R., Chen, T., & Zhang, Z. (2023). Choroidal circulation disturbance is an initial factor in outer retinal degeneration in rats under simulated weightlessness. Frontiers in Physiology, 14, Article 1198862. https://doi.org/10.3389/fphys.2023.1198862
Munster, D. W., Lewandowski, B. E., Nelson, E. S., Prabhu, R. K., & Myers, J. G. (2024). Modeling the impact of thoracic pressure on intracranial pressure. npj Microgravity, 10, Article 46. https://doi.org/10.1038/s41526-024-00385-5
Murgia, M., Rittweger, J., Reggiani, C., Bottinelli, R., Mann, M., Schiaffino, S., & Narici, M. (2024). Spaceflight on the ISS changed the skeletal muscle proteome of two astronauts. npj Microgravity, 10, Article 60. https://doi.org/10.1038/s41526-024-00406-3
Nguyen, H. P., Tran, P. H., Kim, K., & Yang, S. (2021). The effects of real and simulated microgravity on cellular mitochondrial function. npj Microgravity, 7, Article 44. https://doi.org/10.1038/s41526-021-00171-7
Pedriali, G., Ramaccini, D., Bouhamida, E., Więckowski, M. R., Giorgi, C., Tremoli, E., & Pinton, P. (2022). Perspectives on mitochondrial relevance in cardiac ischemia/reperfusion injury. Frontiers in Cell and Developmental Biology, 10, Article 1082095. https://doi.org/10.3389/fcell.2022.1082095
Rudolf, A. M., & Hood, W. R. (2024). Mitochondrial stress in the spaceflight environment. Mitochondrion, 76, Article 101855. https://doi.org/10.1016/j.mito.2024.101855
Russo, S., Di Rasmo, D., Signorile, A., Corcelli, A., & Lobasso, S. (2022). Beneficial effects of SS-31 peptide on cardiac mitochondrial dysfunction in tafazzin knockdown mice. Scientific Reports, 12, Article 19847. https://doi.org/10.1038/s41598-022-24231-4
Shimura, T. (2023). Mitochondrial signaling pathways associated with DNA damage responses. International Journal of Molecular Sciences, 24(7), Article 6128. https://doi.org/10.3390/ijms24076128
Simmons, P., Trujillo, M., McElroy, T., Binz, R. L., Pathak, R., & Allen, A. R. (2022). Evaluating the effects of low-dose simulated galactic cosmic rays on murine hippocampal-dependent cognitive performance. Frontiers in Neuroscience, 16, Article 908632. https://doi.org/10.3389/fnins.2022.908632
Srivastava, V., & Gross, E. (2023). Mitophagy-promoting agents and their ability to promote healthy-aging. Biochemical Society Transactions, 51(5), 1811-1846. https://doi.org/10.1042/BST20221363
Takahashi, A., Honda, Y., Tanaka, N., Miyake, J., Maeda, S., Kataoka, H., Sakamoto, J., & Okita, M. (2024). Skeletal muscle electrical stimulation prevents progression of disuse muscle atrophy via forkhead box O dynamics mediated by phosphorylated protein kinase B and peroxisome proliferator-activated receptor gamma coactivator-1alpha. Physiological Research, 73(1), 105-115. https://doi.org/10.33549/physiolres.935157
Wadhwa, A., Moreno-Villanueva, M., Crucian, B., & Wu, H. (2024). Synergistic interplay between radiation and microgravity in spaceflight-related immunological health risks. Immunity & Ageing, 21, Article 50. https://doi.org/10.1186/s12979-024-00449-w
Waisberg, E., Ong, J., Masalkhi, M., Mao, X. W., Beheshti, A., & Lee, A. G. (2024). Mitochondrial dysfunction in spaceflight associated neuro-ocular syndrome (SANS): A molecular hypothesis in pathogenesis. Eye, 38, 1409-1411. https://doi.org/10.1038/s41433-024-02951-3
Xu, Y., Pei, W., & Hu, W. (2022). A current overview of the biological effects of combined space environmental factors in mammals. Frontiers in Cell and Developmental Biology, 10, Article 861006. https://doi.org/10.3389/fcell.2022.861006
Yang, J., Guo, Q., Feng, X., Liu, Y., & Zhou, Y. (2022). Mitochondrial dysfunction in cardiovascular diseases: Potential targets for treatment. Frontiers in Cell and Developmental Biology, 10, Article 841523. https://doi.org/10.3389/fcell.2022.841523
Yang, Q., Li, C., & Chen, Q. (2022). SS31 ameliorates oxidative stress via the restoration of autophagic flux to protect aged mice from hind limb ischemia. Frontiers in Cardiovascular Medicine, 9, Article 789331. https://doi.org/10.3389/fcvm.2022.789331
Yusri, K., Jose, S., Vermeulen, K., Tan, T. C., & Sorrentino, V. (2025). The role of NAD+ metabolism and its modulation of mitochondria in aging and disease. npj Metabolic Health and Disease, 3, Article 26. https://doi.org/10.1038/s44324-025-00067-0
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Dr. Leah F. Quinto, Dr. Ramon George Atento, Dr. William Dela Cruz, Joel Morcilla, MSMLS, Charmaine O. Castañeda, MS Biology (Author)
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Authors retain copyright of their articles but grant the International Journal of Health & Business Analytics (IJHBA) the right of first publication.
