Maternal Mitochondrial Inheritance

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.

A movie showing paternal mitochondria elimination in a wild-type C. elegans embryo
A movie showing delayed paternal mitochondria elimination in a glo-1(zu391) mutant embryo

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 (Abstract and PDF).

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 (Abstract and PDF). *Equal contribution. #Co-corresponding authors. Science Perspectives, Nature Reviews Molecular Cell Biology, The New York Times, ScienceNews, TheScientist, Le Scienze, Frankfurter Allgemeine, MedicalXpress, Sciences et Avenir, DAGENS Medicin, 新华网, ScienceAlert, Bionews, Faculty of 1000, THE WIRE, THE HINDU, and THE VERGE.

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. (Abstract 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 10, eadp8351 (Abstract and PDF).  Technologynetworks, msn, CU Boulder Today, Hindustan Times, Mirage, News18

Li, S., Redweik, G., Lin, J.L., Chen, Y.N., Yuan, H.S., and Xue, D. (2024). Probing the importance of AIF interaction with endonuclease G in mitochondrial inheritance and neurodegeneration. Cell Discovery 10, 107 (Abstract and PDF).

Wang, S. and Xue, D. (2025). Asymmetric partitioning of persistent paternal mitochondria during cell divisions safeguards embryo development and mitochondrial inheritance. Developmental Cell 60 1-21 (Abstract and PDF)

Patents

Ding Xue and Hu Zhang, Provisional Patent Application 63/702,789. Title "Compositions and methods for the treatment of delayed paternal mitochondrial elimination (PME)” (filed on 10/03/2024)