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Mitochondrial Fission Factor Drp1 Maintains Oocyte Quality via Dynamic Rearrangement of Multiple Organelles

2014; Elsevier BV; Volume: 24; Issue: 20 Linguagem: Inglês

10.1016/j.cub.2014.08.060

1879-0445

Osamu Udagawa, Takaya Ishihara, Maki Maeda, Yui Matsunaga, Satoshi Tsukamoto, Natsuko Kawano, Kenji Miyado, Hiroshi Shitara, Sadaki Yokota, Masatoshi Nomura, Katsuyoshi Mihara, Noboru Mizushima, Naotada Ishihara,

CRISPR and Genetic Engineering

Mitochondria are dynamic organelles that change their morphology by active fusion and fission in response to cellular signaling and differentiation [1McBride H.M. Neuspiel M. Wasiak S. Mitochondria: more than just a powerhouse.Curr. Biol. 2006; 16: R551-R560Abstract Full Text Full Text PDF PubMed Scopus (1378) Google Scholar, 2Ishihara N. Otera H. Oka T. Mihara K. Regulation and physiologic functions of GTPases in mitochondrial fusion and fission in mammals.Antioxid. Redox Signal. 2013; 19: 389-399Crossref PubMed Scopus (52) Google Scholar]. The in vivo role of mitochondrial fission in mammals has been examined by using tissue-specific knockout (KO) mice of the mitochondria fission-regulating GTPase Drp1 [3Ishihara N. Nomura M. Jofuku A. Kato H. Suzuki S.O. Masuda K. Otera H. Nakanishi Y. Nonaka I. Goto Y. et al.Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice.Nat. Cell Biol. 2009; 11: 958-966Crossref PubMed Scopus (749) Google Scholar, 4Wakabayashi J. Zhang Z. Wakabayashi N. Tamura Y. Fukaya M. Kensler T.W. Iijima M. Sesaki H. The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice.J. Cell Biol. 2009; 186: 805-816Crossref PubMed Scopus (457) Google Scholar], as well as analyzing a human patient harboring a point mutation in Drp1 [5Waterham H.R. Koster J. van Roermund C.W. Mooyer P.A. Wanders R.J. Leonard J.V. A lethal defect of mitochondrial and peroxisomal fission.N. Engl. J. Med. 2007; 356: 1736-1741Crossref PubMed Scopus (584) Google Scholar], showing that Drp1 is essential for embryonic and neonatal development and neuronal function. During oocyte maturation and aging, structures of various membrane organelles including mitochondria and the endoplasmic reticulum (ER) are changed dynamically [6Sundström P. Nilsson B.O. Liedholm P. Larsson E. Ultrastructure of maturing human oocytes.Ann. N Y Acad. Sci. 1985; 442: 324-331Crossref PubMed Scopus (18) Google Scholar, 7Dalton C.M. Carroll J. Biased inheritance of mitochondria during asymmetric cell division in the mouse oocyte.J. Cell Sci. 2013; 126: 2955-2964Crossref PubMed Scopus (112) Google Scholar], and their organelle aggregation is related to germ cell formation and epigenetic regulation [8Pepling M.E. Wilhelm J.E. O’Hara A.L. Gephardt G.W. Spradling A.C. Mouse oocytes within germ cell cysts and primordial follicles contain a Balbiani body.Proc. Natl. Acad. Sci. USA. 2007; 104: 187-192Crossref PubMed Scopus (173) Google Scholar, 9Watanabe T. Chuma S. Yamamoto Y. Kuramochi-Miyagawa S. Totoki Y. Toyoda A. Hoki Y. Fujiyama A. Shibata T. Sado T. et al.MITOPLD is a mitochondrial protein essential for nuage formation and piRNA biogenesis in the mouse germline.Dev. Cell. 2011; 20: 364-375Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 10Wai T. Teoli D. Shoubridge E.A. The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes.Nat. Genet. 2008; 40: 1484-1488Crossref PubMed Scopus (332) Google Scholar]. However, the underlying molecular mechanisms of organelle dynamics during the development and aging of oocytes have not been well understood. Here, we analyzed oocyte-specific mitochondrial fission factor Drp1-deficient mice and found that mitochondrial fission is essential for follicular maturation and ovulation in an age-dependent manner. Mitochondria were highly aggregated with other organelles, such as the ER and secretory vesicles, in KO oocyte, which resulted in impaired Ca2+ signaling, intercellular communication via secretion, and meiotic resumption. We further found that oocytes from aged mice displayed reduced Drp1-dependent mitochondrial fission and defective organelle morphogenesis, similar to Drp1 KO oocytes. On the basis of these findings, it appears that mitochondrial fission maintains the competency of oocytes via multiorganelle rearrangement.