Post-fertilisation sperm mitophagy: the tale of Mitochondrial Eve and Steve

Preformationist William Harvey’s proclamation of everything live coming from an egg still holds true for mammalian mitochondria and mitochondrial genes. At fertilisation, mitochondria carried into the oocyte cytoplasm by the spermatozoon are sought out and destroyed, leaving only oocyte mitochondria to propagate their mitochondrial (mt) DNA to offspring. This clonal inheritance mode, the ‘mitochondrial Eve’ paradigm, is mediated by oocytes’ resident proteolytic, organelle-targeting mechanisms, including the substrate-specific ubiquitin proteasome system and the autophagic machinery for bulk protein and organelle degradation. Ubiquitination of sperm mitochondria within the cytoplasm of the fertilised oocyte was initially discovered in mammals. More recent studies in Drosophila and Caenorhabditis elegans implicated the ubiquitin-binding autophagy protein sequestosome 1 (SQSTM1) as the early adaptor channelling ubiquitinated sperm mitochondria towards the autophagic machinery. Downstream receptors include microtubule-associated protein 1 light chain 3α (LC3) and GABA type A receptor-associated protein (GABARAP). Among mammals, the domestic pig is the ideal mammalian model of mitochondrial inheritance because of rapid sperm mitophagy at the 1-cell stage of embryo development. Primary recognition of sperm mitochondria by SQSTM1 inside the porcine zygote is followed by GABARAP-containing autophagophore formation, and contributed to by valosin-containing protein (VCP), a 26S proteasome-presenting protein dislocase. Consequently, coinhibition of SQSTM1–GABARAP and VCP activities in the porcine zygotes, resulting in 2- to 4-cell embryos carrying intact sperm mitochondrial sheaths, revived the moniker of ‘Mitochondrial Steve’. Further work will identify the determinants of species specificity of sperm mitophagy and explain the interplay and possible consequences of a mismatch between clonal mitochondrial genome and biparentally inherited chromosomal genes encoding for structural mitochondrial proteins and transcription factors. By better understanding sperm mitophagy and its potential failure, we may be able to alleviate mitochondrial disease and early pregnancy loss in livestock and improve their fitness, reproduction and ability to pass favourable production traits to offspring.