Convergent Evolution of MT-ND1 Ubiquinone Gatekeeper Signature in Exceptionally Long-Lived Vertebrates

Oxidative stress and mitochondrial dysfunction are hallmarks of aging and major contributors to age-related disease. Yet the structural and functional determinants within respiratory Complex I that maycontribute to species-specific differences in longevity remain poorly understood. Using comparativegenomic, evolutionary, and structural analyses, I identified a conserved primate ubiquinonegatekeeper signature (Met17/Met21/Met225) within mitochondrially encoded NADH dehydrogenasesubunit 1 (MT-ND1), positioned at the entrance to the respiratory Complex I ubiquinone accesschannel. Remarkably, multiple exceptionally long-lived vertebrate lineages, including bats,cetaceans, birds, marsupials, monotremes, and coelacanth, independently evolved a sharedVal17/Thr21/Leu225 gatekeeper signature at this site. Cartilaginous fishes exhibit a closely relatedThr17/Thr21/Leu225 gatekeeper signature. Structural mapping places these residues within the MT-ND1 ubiquinone access pathway, where oxidative modification could influence ubiquinone access,electron transfer, and reactive oxygen species (ROS) generation. This region overlaps with thepharmacologically important ubiquinone-binding site targeted by numerous Complex I inhibitors.Their recurrent replacement in evolutionarily distant, exceptionally long-lived vertebrates isconsistent with reduced oxidative vulnerability of Complex I. Together, these observations support amodel in which oxidation-prone MT-ND1 methionines contribute to mitochondrial oxidativevulnerability, whereas their recurrent evolutionary replacement may promote mitochondrial redoxhomeostasis. These findings identify the MT-ND1 ubiquinone gatekeeper signature as a previouslyunrecognized molecular nexus linking respiratory chain architecture, therapeutic response, andvertebrate longevity.