Abstract
A defining feature of mitochondria is their maternal mode of inheritance. However, little is understood about the cellular mechanism through which paternal mitochondria, delivered from sperm, are eliminated from early mammalian embryos. Autophagy has been implicated in nematodes, but whether this mechanism is conserved in mammals has been disputed. Here, we show that cultured mouse fibroblasts and pre-implantation embryos use a common pathway for elimination of mitochondria. Both situations utilize mitophagy, in which mitochondria are sequestered by autophagosomes and delivered to lysosomes for degradation. The E3 ubiquitin ligases PARKIN and MUL1 play redundant roles in elimination of paternal mitochondria. The process is associated with depolarization of paternal mitochondria and additionally requires the mitochondrial outer membrane protein FIS1, the autophagy adaptor P62, and PINK1 kinase. Our results indicate that strict maternal transmission of mitochondria relies on mitophagy and uncover a collaboration between MUL1 and PARKIN in this process.
Highlights
In most animals, including mammals, mitochondria are inherited strictly through the maternal lineage
We examined the efficiency of OXPHOS-induced mitophagy in a panel of mouse embryonic fibroblasts (MEFs) cell lines deficient in mitochondrial fusion or fission genes: Mitofusin 1 (Mfn1), Mitofusin 2 (Mfn2), both Mfn1 and Mfn2 (Mfn-dm), Optic atrophy 1 (Opa1), Mitochondrial fission factor (Mff), Dynamin-related protein 1 (Drp1), and Mitochondrial fission 1 (Fis1) (Figure 3A)
We found a similar redundancy of MUL1 and PARKIN function in mitophagy induced by depolarization of mitochondria with CCCP (Figure 4—figure supplement 1D)
Summary
In most animals, including mammals, mitochondria are inherited strictly through the maternal lineage. Because sperm deliver mitochondria into the egg during fertilization, mechanisms likely exist to eliminate paternal mitochondria from the early embryo. Uniparental inheritance of mitochondria ensures that only one haplotype of mitochondrial DNA (mtDNA) exists in the offspring, a phenomenon with considerable biomedical implications. It underlies the maternal inheritance of diseases caused by mutations in mtDNA (Carelli and Chan, 2014) and enables the use of mtDNA sequences to track human migrations during evolution. It is unclear to what extent these insights from invertebrate model organisms extend to mammals.
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