In most eukaryotes, the inheritance of mitochondrion and its DNA (mtDNA) is strictly maternal, despite the fact that a spermatozoon can inject up to 100 functional mitochondria into the oocyte during fertilization. The mechanisms responsible for selective elimination of paternal mitochondria have been a major question in developmental biology. We initiated study of this fascinating process in?C.?elegans?and developed a sensitive PCR-based assay and a fluorescent microscopy assay to track the fate of paternal mitochondria in fertilized oocytes, starting from the entry of sperm miotochondria into the oocyte to their eventual elimination. We found that the paternal mitochondrial elimination process (PME) is conserved in?C.?elegans?and that the maternal autophagy/lysosomal?pathway and the proteasome degradation pathway actively participate in the PME process (Zhou et al.,?Cell Research?2011). We have performed several RNAi screens and candidate-based screens to identify maternal and paternal factors important for paternal mitochondrial elimination and have identified multiple genes important for PME, including a mitochondrial nuclease, endonuclease G, that mediates paternal mitochondrial self-destruction right after fertilization (Zhou et al.,?Science?2016) and two mitochondrial GTPases, DRP-1 and FZO-1, that act paternally and maternally, respectively, to regulate the kinetics and specificity of paternal mitochondrial elimination (Wang et al.,?Nature Communications?2016). We also demonstrate that delayed removal of paternal mitochondria leads to decreased fitness at the cellular and organismal levels and presents an evolutionary disadvantage (Zhou et al.,?Science?2016). Genetic, cell biological, and biochemical characterization of the identified genes involved in PME will help reveal signals that mark sperm mitochondria for destruction and the signaling pathways that recognize the signals to activate the maternal degradation machineries. Understanding of these important questions will be critical for treating various inherited human mitochondrial disease and for determining the safety and efficiency of animal cloning involving spermatid or sperm microinjection.
Related Publications:
Zhou, Q.H., Li, H.M., and Xue, D. (2011).?Elimination of Paternal mitochondria through the?lysosomal?degradation pathway in?C.?elegans.?Cell Research?21, 1662-1669 (?and?).
Zhou, Q.H.*, Li, H.M.*, Li, H.Z.*, Nakagawa, A., Harry, B., Lee, E.S., Lin, J., William, D., Mitani, S., Yuan, H., Kang, B.H.#, and Xue, D.# (2016). Mitochondrial endonuclease G mediates breakdown of paternal mitochondria following fertilization.?Science?353, 394-399 (?and?PDF). *Equal contribution. #Co-corresponding authors.?Science Perspectives,?Nature Reviews Molecular Cell Biology,?,?,?,?,?,?,?,?,?,?,?,?,?, and?
Wang, Y.*, Zhang, Y.*, Chen, L.W., Liang, Q., Yin, X.M., Miao, L., Kang, B.H.#, and Xue, D.# (2016). Kinetics and specificity of paternal mitochondrial elimination in?Caenorhabditis elegans.?Nature Communications?7, 12569. DOI: 10.1038/ncomms12569. (?and?PDF). *Equal contribution. #Co-corresponding authors.
Zhang, H., Zhu, Y., and Xue, D. (2024). Moderate embryonic delay of paternal mitochondrial elimination impairs mating and cognition and alters behaviors of adult animals. Science Advances, in press.