Oocyte mitophagy is critical for extended reproductive longevity

Women’s reproductive cessation is the earliest sign of human aging and is caused by decreasing oocyte quality. Similarly, C. elegans’ reproduction declines in mid-adulthood and is caused by oocyte quality decline. Aberrant mitochondrial morphology is a hallmark of age-related dysfunction, but the role of mitochondrial morphology and dynamics in reproductive aging is unclear. We examined the requirements for mitochondrial fusion and fission in oocytes of both wild-type worms and the long-lived, long-reproducing insulin-like receptor mutant daf-2. We find that normal reproduction requires both fusion and fission, but that daf-2 mutants utilize a shift towards fission, but not fusion, to extend their reproductive span and oocyte health. daf-2 mutant oocytes’ mitochondria are punctate (fissioned) and this morphology is primed for mitophagy, as loss of the mitophagy regulator PINK-1 shortens daf-2’s reproductive span. daf-2 mutants maintain oocyte mitochondria quality with age at least in part through a shift toward punctate mitochondrial morphology and subsequent mitophagy. Supporting this model, Urolithin A, a metabolite that promotes mitophagy, extends reproductive span in wild-type mothers–even in mid-reproduction—by maintaining youthful oocytes with age. Our data suggest that promotion of mitophagy may be an effective strategy to maintain oocyte health with age.Author summary: Female reproductive decline begins in a woman’s 30’s, and has become an increasingly important area of research as more women delay child bearing. Like women, the nematode C. elegans undergoes reproductive senescence starting in mid-life, and its reproductive span is determined by oocyte quality decline with age. One of the hallmarks of aging is an increase in mitochondrial dysfunction that can be driven by aberrant mitochondrial fission and fusion, the main regulators of metabolic function and mitochondrial dynamics. In this study we identified a mechanism that promotes reproductive longevity using mitochondrial fission and mitophagy, the trash compactor of dysfunctional mitochondria. This mechanism led us to test Urolithin A, a common metabolite that promotes mitophagy and extends lifespan in C. elegans, as a possible therapeutic to delay reproductive decline. We suggest promotion of mitophagy in oocytes as a new target to extend reproductive longevity through Urolithin A supplementation.