The article discusses the potential role of mitochondrial dysfunction in the development of Spaceflight-Associated Neuro-Ocular Syndrome (SANS), a condition affecting astronauts during long-duration spaceflight (LDSF). SANS is characterized by hyperopic refractive shifts, optic disc edema, globe flattening, and chorioretinal folds. While traditional hypotheses attribute SANS to fluid shifts and structural changes in the eye caused by microgravity, recent research highlights the importance of mitochondrial dysfunction. Microgravity and exposure to galactic cosmic radiation can significantly impact mitochondrial function, leading to altered gene expression, reduced antioxidant defenses, and increased oxidative stress. Mitochondria play a crucial role in energy production, apoptosis regulation, and maintaining cellular homeostasis, particularly in the retina. Studies have shown that spaceflight conditions induce mitochondrial oxidative damage in ocular tissue, with elevated levels of 4-hydroxynonenal and significant apoptosis in the retina. Additionally, B-vitamin status and 1-carbon metabolites, such as homocysteine, are important factors affecting mitochondrial function and potentially contributing to SANS. Understanding these mechanisms is crucial for developing effective countermeasures to mitigate the risks associated with long-duration space missions, including lifestyle and pharmacological interventions.The article discusses the potential role of mitochondrial dysfunction in the development of Spaceflight-Associated Neuro-Ocular Syndrome (SANS), a condition affecting astronauts during long-duration spaceflight (LDSF). SANS is characterized by hyperopic refractive shifts, optic disc edema, globe flattening, and chorioretinal folds. While traditional hypotheses attribute SANS to fluid shifts and structural changes in the eye caused by microgravity, recent research highlights the importance of mitochondrial dysfunction. Microgravity and exposure to galactic cosmic radiation can significantly impact mitochondrial function, leading to altered gene expression, reduced antioxidant defenses, and increased oxidative stress. Mitochondria play a crucial role in energy production, apoptosis regulation, and maintaining cellular homeostasis, particularly in the retina. Studies have shown that spaceflight conditions induce mitochondrial oxidative damage in ocular tissue, with elevated levels of 4-hydroxynonenal and significant apoptosis in the retina. Additionally, B-vitamin status and 1-carbon metabolites, such as homocysteine, are important factors affecting mitochondrial function and potentially contributing to SANS. Understanding these mechanisms is crucial for developing effective countermeasures to mitigate the risks associated with long-duration space missions, including lifestyle and pharmacological interventions.