Maternal inheritance of mitochondria and mtDNA is a universal principle in human and animal development, guided by selective ubiquitin-dependent degradation of the sperm-borne mitochon-dria after fertilization. However, it is not clear how the 26S pro-teasome, the ubiquitin-dependent protease that is only capable of degrading one protein molecule at a time, can dispose of a whole sperm mitochondrial sheath. We hypothesized that the canonical ubiquitin-like autophagy receptors [sequestosome 1 (SQSTM1), microtubule-associated protein 1 light chain 3 (LC3), gamma-aminobutyric acid receptor-associated protein (GABARAP)] and the nontraditional mitophagy pathways involving ubiquitin-proteasome system and the ubiquitin-binding protein dislocase, valosin-containing protein (VCP), may act in concert during mam-malian sperm mitophagy. We found that the SQSTM1, but not GABARAP or LC3, associated with sperm mitochondria after fertilization in pig and rhesus monkey zygotes. Three sperm mitochondrial proteins copurified with the recombinant, ubiquitin-associated domain of SQSTM1. The accumulation of GABARAP-containing protein aggregates was observed in the vicinity of sperm mitochondrial sheaths in the zygotes and increased in the embryos treated with proteasomal inhibitor MG132, in which intact sperm mitochondri-al sheaths were observed. Pharmacological inhibition of VCP significantly delayed the process of sperm mitophagy and completely prevented it when combined with microinjection of autophagy-targeting antibodies specific to SQSTM1 and/or GABARAP. Sperm mitophagy in higher mammals thus relies on a combined action of SQSTM1-dependent autophagy and VCP-mediated dislocation and presentation of ubiquitinated sperm mitochondrial proteins to the 26S proteasome, explaining how the whole sperm mitochondria are degraded inside the fertilized mammalian oocytes by a protein recycling system involved in degradation of single protein molecules. mitochondria | mtDNA | ubiquitin | autophagy | mitophagy T he inheritance pattern of the mitochondrial genome does not follow Mendelian rules as mtDNA is predominantly or exclusively inherited from the mother in almost all eukaryotic species studied, which is referred to as maternal inheritance of mtDNA (1, 2). The proteolytic ubiquitin-proteasome system (UPS) for substrate-specific, regulated protein recycling has been implicated in the targeted degradation of paternal mi-tochondria (sperm mitophagy) in mammals and other taxa. Mammalian sperm mitochondria are already modified with ubiquitin during spermatogenesis and ultimately processed by proteasome-mediated proteolysis (3). Specific cell-permeant inhibitors of proteasomal chymotrypsin-like activity, MG132 and lactacystin, blocked the progression of sperm mitophagy after porcine fertilization, and the resumption of sperm mi-tochondrion degradation was observed once the MG132 (a reversible inhibitor) was removed from the zygotes (4). Our early study reported that sperm tails in zygotes were surrounded by lysosome-like structures, which sugge...
Exposure to BaP decreases the fertilization potential of exposed males and has an adverse impact on sperm function and fertility in subsequent generations. The BaP effect on fertility can be described as a transgenerational effect for F2 generation.
This article discusses the historical perspective and the new findings of autophagy and ubiquitin-proteasome system cooperation during the post-fertilization sperm mitophagy, a process that eliminates potentially damaged paternal mitochondrial DNA from an early embryo. New insight into the mechanism that promotes clonal, maternal inheritance of mitochondrial genes may be helpful for managing mitochondrial disease and infertility in humans, as well as reproductive performance and production traits in agriculturally important domestic animals.
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