Oocyte Mitophagy in Reproductive Aging

In many species, aging of the female reproductive system occurs more rapidly than is the case for other parts of the body. This is one of a few biological systems subject to what appears to be premature aging, relative to other organs. Other examples include the thymus, which atrophies well before late life. Researcher here suggest that mitochondrial quality control, the process of mitophagy, is involved in the aging of oocytes to a great enough degree that upregulation of mitophagy may delay female reproductive aging.

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.

Link: https://doi.org/10.1371/journal.pgen.1010400

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