Mitophagy at the oocyte-to-zygote transition promotes species immortality

Abstract

The quality of inherited mitochondria determines embryonic viability1, metabolic health during adulthood and future generation endurance. The oocyte is the source of all zygotic mitochondria2, and mitochondrial health is under strict developmental regulation during early oogenesis3-5. Yet, fully developed oocytes exhibit the presence of deleterious mitochondrial DNA (mtDNA)6,7 and mitochondrial dysfunction from high levels of endogenous reactive oxygen species8 and exogenous toxicants9. How fully developed oocytes prevent transmission of damaged mitochondria to the zygotes is unknown. Here we discover that the onset of oocyte-to-zygote transition (OZT) developmentally triggers a robust and rapid mitophagy event that we term mitophagy at OZT (MOZT). We show that MOZT requires mitochondrial fragmentation, activation of the macroautophagy system and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. Oocytes upregulate expression of FUNDC1 in response to diverse mitochondrial insults, including mtDNA mutations and damage, uncoupling stress, and mitochondrial dysfunction, thereby promoting selection against damaged mitochondria. Loss of MOZT leads to increased inheritance of deleterious mtDNA and impaired bioenergetic health in the progeny, resulting in diminished embryonic viability and the extinction of descendent populations. Our findings reveal FUNDC1-mediated MOZT as a mechanism that preserves mitochondrial health during the mother-to-offspring transmission and promotes species continuity. These results may explain how mature oocytes from many species harboring mutant mtDNA give rise to healthy embryos with reduced deleterious mtDNA.