Autophagy and ubiquitin-proteasome system during post-fertilization sperm mitophagy
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Maternal inheritance of mitochondria and mitochondrial DNA (mtDNA) is a universal principle in developmental biology. Mammalian sperm-borne mitochondria are selectively degraded inside the fertilized oocyte. Our early observations established that post-fertilization degradation of sperm mitochondria is mediated by ubiquitin-proteasome system (UPS), the major protein-turnover pathway that degrades proteins one molecule at a time. Others' recent studies suggested that a whole organelle sperm mitochondrion is degraded by autophagic pathway, which is referred to as sperm mitophagy. Based on this understanding, the first objective of this dissertation was to identify UPS determinants present in porcine sperm mitochondria. The second objective was to characterize the UPS-controlled porcine ooplasmic autophagy receptors that may regulate sperm mitophagy after fertilization. The interaction between UPS and autophagic pathway was revealed during post-fertilization sperm mitophagy. It was determined that the ooplasmic, ubiquitin-binding autophagy receptor SQSTM1 binds to ubiquitinated mitochondrial membrane proteins, targeting whole mitochondria towards autophagosome. Concurrently, protein dislocase VCP extracts ubiquitinated mitochondrial membrane proteins and transport them to proteasome. Collectively, these studies offer insight into the mechanisms guiding sperm mitochondrion recognition and disposal after fertilization, which assure normal preimplantation development and prevent a potentially detrimental effect of heteroplasmy.
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