Spaceflight-associated neuro-ocular syndrome (SANS) is a condition affecting astronauts during long-duration spaceflight (LDSF), characterized by hyperopic refractive shifts, optic disc edema, globe flattening, and chorioretinal folds. As space travel increases, the risk of SANS may rise, especially with future missions like the 2030 Mars mission. While traditional theories link SANS to fluid shifts and structural changes in the eye due to microgravity, recent research suggests mitochondrial dysfunction may be a key factor. Microgravity and cosmic radiation significantly impact mitochondrial function, leading to mitochondrial stress, altered gene expression, and increased oxidative stress. Mitochondria are crucial for energy production and cellular homeostasis, and their dysfunction can lead to retinal damage. The retina, with its high oxygen consumption and exposure to light, is particularly vulnerable to oxidative damage. Mitochondrial defects are associated with eye diseases like diabetic retinopathy and age-related macular degeneration, as well as Leber hereditary optic neuropathy. Microgravity can alter cellular signaling pathways, leading to mitochondrial dysfunction and cellular damage. Spaceflight also exposes astronauts to increased oxidative stress and ionizing radiation, further compromising mitochondrial function. Studies show that spaceflight induces mitochondrial oxidative damage in ocular tissue, with increased 4-hydroxynonenal (4-HNE) levels and apoptosis in retinal cells. B-vitamin status is a significant predictor of visual outcomes after spaceflight, and imbalances in 1-carbon metabolites like homocysteine may contribute to mitochondrial dysfunction. Potential countermeasures for SANS include intraocular pressure modulation, augmented reality, and near-infrared light therapy. Improved diagnostics are also needed to detect subtle retinal changes during spaceflight. Understanding the link between mitochondrial dysfunction and SANS is crucial for developing effective countermeasures to mitigate risks during long-duration space missions.Spaceflight-associated neuro-ocular syndrome (SANS) is a condition affecting astronauts during long-duration spaceflight (LDSF), characterized by hyperopic refractive shifts, optic disc edema, globe flattening, and chorioretinal folds. As space travel increases, the risk of SANS may rise, especially with future missions like the 2030 Mars mission. While traditional theories link SANS to fluid shifts and structural changes in the eye due to microgravity, recent research suggests mitochondrial dysfunction may be a key factor. Microgravity and cosmic radiation significantly impact mitochondrial function, leading to mitochondrial stress, altered gene expression, and increased oxidative stress. Mitochondria are crucial for energy production and cellular homeostasis, and their dysfunction can lead to retinal damage. The retina, with its high oxygen consumption and exposure to light, is particularly vulnerable to oxidative damage. Mitochondrial defects are associated with eye diseases like diabetic retinopathy and age-related macular degeneration, as well as Leber hereditary optic neuropathy. Microgravity can alter cellular signaling pathways, leading to mitochondrial dysfunction and cellular damage. Spaceflight also exposes astronauts to increased oxidative stress and ionizing radiation, further compromising mitochondrial function. Studies show that spaceflight induces mitochondrial oxidative damage in ocular tissue, with increased 4-hydroxynonenal (4-HNE) levels and apoptosis in retinal cells. B-vitamin status is a significant predictor of visual outcomes after spaceflight, and imbalances in 1-carbon metabolites like homocysteine may contribute to mitochondrial dysfunction. Potential countermeasures for SANS include intraocular pressure modulation, augmented reality, and near-infrared light therapy. Improved diagnostics are also needed to detect subtle retinal changes during spaceflight. Understanding the link between mitochondrial dysfunction and SANS is crucial for developing effective countermeasures to mitigate risks during long-duration space missions.