Humanin as an evolutionarily tuned mitochondrial peptide: Insights from mammalian oxidative stress diversity

Humanin is a mitochondrial-derived peptide with cytoprotective properties, but how it has evolved in response to different oxidative stress levels in mammals is not fully understood. This study examines how Humanin sequences have adapted to species-specific metabolic and environmental pressures. We compared the peptide in several mammalian species categorized by their distinct oxidative stress profiles: small mammals such as shrews with high metabolic rates and elevated endogenous ROS production, cetaceans exposed to hypoxia-reoxygenation cycles during deep diving, and long-lived primates facing cumulative oxidative stress over extended lifespans. Using bioinformatic tools, we analyzed physicochemical traits such as structural stability, the aliphatic index, and oxidation susceptibility. We also used protein-protein docking to estimate binding affinities between Humanin variants and key ligands like BAX and FPRL1. Our results show that Humanin is not a static molecule. Species facing high oxidative stress, such as cetaceans and bats, possess variants that are more stable and chemically robust. In contrast, species with high ROS production but lower antioxidant capacity, like the shrew, have less robust versions of the peptide. Simulation data indicate that variants from mammals living in extreme conditions maintain or improve interactions with proteins involved in cell survival. These findings suggest that evolution has tuned Humanin to optimize mitochondrial protection across different physiological contexts. These natural isoforms provide a structural basis for designing new therapeutic analogs to treat oxidative stress-related diseases in humans.