Reframing spaceflight-associated neuro-ocular syndrome as spaceflight-associated optic neuropathy (SAON):...

Spaceflight-Associated Neuro-Ocular Syndrome (SANS) has remained poorly understood throughout the history of human spaceflight despite being classified as the largest physiologic barrier that astronauts face. Existing mechanistic explanations of SANS are limited in accounting for its tissue specificity, interindividual heterogeneity, and persistence beyond return to Earth, which has left countermeasure development without a coherent biological target. Through integration of tissue-resolved murine spaceflight transcriptomic datasets with human retinal ganglion cell models of Leber Hereditary Optic Neuropathy (LHON), we define a share pattern of injury underlying SANS. Across all datasets, suppression of mitochondrial oxidative phosphorylation (OXPHOS) consistently preceded innate immune, interferon, and PANoptotic activation, establishing metabolic collapse as the initiating event rather than a downstream consequence. Strain-dependent divergence in mitochondrial resilience between BALB/c and C57BL/6 J mice onboard the International Space Station (ISS) supports a threshold-dependent susceptibility model, and cross-species convergence with LHON-derived retinal ganglion cells identifies shared molecular signatures linking spaceflight neurodegeneration with terrestrial mitochondrial optic neuropathies. These findings support reclassification of SANS as a mitochondrial-inflammatory optic neuropathy, spaceflight-associated optic neuropathy (SAON), providing the first mechanistically complete basis for countermeasure development, risk stratification, and an evolution from syndromic classification towards a defined disease framework.