Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology

Just Accepted

This article has been peer reviewed and accepted for publication. It is in production and has not been edited, so may differ from the final published form.

Post-fertilization Sperm Mitophagy: The Tale of Mitochondrial Eve and Steve

Peter Sutovsky


Preformationist William Harvey’s proclamation of everything live coming from an egg still holds true for mammalian mitochondria and mitochondrial genes. At fertilization, the mitochondria carried into oocyte cytoplasm by the fertilizing spermatozoon are sought out and destroyed, leaving only oocyte mitochondria to propagate their mtDNA to offspring. This clonal inheritance mode, the “mitochondrial Eve” paradigm is mediated by oocytes’ resident proteolytic, organelle-targeting mechanisms including substrate-specific ubiquitin-proteasome system (UPS) and the autophagic/mitophagic machinery for bulk protein and organelle degradation. Sperm mitochondrion ubiquitination within the fertilized oocyte cytoplasm was initially discovered in mammals, and shown to be sensitive to inhibitors of the 26S proteasome, the ubiquitin-dependent protease holoenzyme, and contributed by lysosomal proteolysis. More recent studies in Drosophila and C. elegans implicated the ubiquitin-binding autophagy protein SQSTM1 as the early adaptor channeling ubiquitinated sperm mitochondria towards autophagophore, the isolation membrane, transformed into autophagosome, and ultimately autolysosome after fusion with a lysosome. Downstream autophagy receptors in this pathway include LC3 and GABARAP. Among mammals, domestic pig is the ideal mammalian model because of rapid sperm mitophagy at one cell stage of embryo development. Primary recognition of sperm mitochondria by SQSTM1 inside the porcine zygote is followed by GABARAP-containing autophagophore formation and autophagy. The process is contributed by protein dislocase VCP, extracting ubiquitinated proteins from sperm mitochondrial membranes for presentation to the 26S proteasome. Consequently, the co-inhibition of SQSTM1-GABARAP and VCP activities in the porcine zygotes resulted in 2-4 cell embryos carrying intact sperm mitochondrial sheaths (MS), reviving the moniker of “mitochondrial Steve”. Further work in mammalian zygotes, embryos and cell free systems aims to identify the determinants of species specificity of sperm mitophagy, and understand the interplay and possible mismatch consequences between clonal mitochondrial genome and biparentally inherited chromosomal genes encoding for structural mitochondrial proteins and mitochondrial transcription factors. A recent alternative theory of the “DNA empty” sperm mitochondria in mice and Drosophila is contradicted by studies of sperm mtDNA copy number and by established paternal mtDNA transmission in interspecies and interstrain crosses. 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, reproductive performance and ability to pass favorable mitochondrion-influenced production traits onto offspring.

RD17364  Accepted 02 October 2017

© CSIRO 2017