Sociality shapes mitochondrial adaptations supporting hypoxia tolerance

Abstract

Oxygen deprivation or hypoxia is poorly dealt with by most terrestrial species and often leads to permanent tissue damage and death. One prominent exception is the naked mole-rat (Heterocephalus glaber) which is remarkably adapted to withstand prolonged periods ([~]18 mins) of severe hypoxia, a trait likely driven by its crowded underground lifestyle. Other African mole-rat species are less social or entirely solitary like the Cape mole-rat (Georychus capensis). Here, we asked whether cellular and molecular adaptations to hypoxia map to social traits. We discovered that at the cellular level naked mole-rat fibroblasts survive >30 hours in 1% oxygen, while fibroblasts from terrestrial or non-social mole-rat species (human, mouse and Cape mole-rat) die rapidly under hypoxic conditions. We further show that naked mole-rat mitochondria have evolved morphological, functional and proteomic adaptations crucial for hypoxia resistance, remaining unaffected after long periods of severe hypoxia. We identify the mitochondrial protein Optic Atrophy 1 (OPA1) as a key player in naked mole-rat hypoxia resilience. Naked mole-rat mitochondria not only express more protective forms of OPA1, but also harbor a structurally unique isoform that likely protects cells from hypoxic damage. We show that evolutionary changes including the functionalization of a unique Opa1 exon support mitochondrial mediated cellular protection. Indeed, knockdown of OPA1 in naked mole-rat cells is sufficient to render them equally susceptible to hypoxia as human cells or cells from non-social African species. Our study demonstrates how molecular evolution drives unique adaptations that enable cells to achieve unprecedented resistance to hypoxic damage. We also show that molecular changes at the level of mitochondria are crucial in conferring hypoxia resistance. Our results thus chart a novel molecular path to understand how robust cellular hypoxia resistance can be achieved. Such knowledge may eventually inspire novel strategies to circumvent the consequences of hypoxic-damage in humans.