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Molecular Mechanisms and Physiological Roles of Mitochondrial Fusion and Division
Our laboratory is interested in the molecular mechanisms and physiological roles of mitochondrial fusion. Mitochondria are highly dynamic and control their morphology by a balance of fusion and fission. The regulation of membrane fusion and fission generates a striking diversity of mitochondrial shapes, ranging from numerous small spheres in hepatocytes to long branched tubules in myotubes. In addition to shape and number, mitochondrial fusion is critical for normal organelle function. For example, mice that are defective in mitochondrial fusion die during early development while yeast fusion mutants rapidly lose their mitochondria genome and become incapable of oxidative phosphorylation. Moreover, mitochondrial fusion also regulates the release of cytochrome C during apoptosis. Therefore, it is not surprising that defects in mitochondrial fusion cause neurodegenerative disorders in humans, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. Using yeast as a model system, we have identified several components that mediate and regulate mitochondrial fusion. We are currently trying to determine their functions in both yeast and mammals. The goals of our research are to understand the molecular basis of mitochondria fusion using biochemical approaches and to determine the physiological roles of mitochondrial fusion using cell culture and animal models.
Kageyama, Y., Zhang, Z., and Sesaki, H. (2011). Mitochondrial division: molecular machinery and physiological functions.Curr. Opin. Cell Biol. In press.
Zhang, Z., Wakabayashi, N., Wakabayashi, J., Tamura, Y., Song, W.-J., Sereda, S., Clerc, P., Polster, B.M., Aja, S.M., Pletnikov, M.V., Kensler, T.W., Shirihai, O.S., Iijima, M., Hussain, M., and Sesaki, H. (2011). The Dynamin-related GTPase Opa1 is required for glucose-stimulated ATP production in pancreatic beta cells. Mol. Biol. Cell. 22: 2235-2245.
Itoh, K., Tamura, Y., and Sesaki, H. (2011). SnapShot: Mitochondrial dynamics. Cell.145:1158-11581e.
Wang, Y., Steimle, P.A., Ren, Y., Ross, C.A., Robinson, D.N., Egelhoff, T.T., Sesaki, H., and Iijima, M. (2011). Dictyostelium huntingtin controls chemotaxis and cytokinesis through the regulation of myosin II phosphorylation. Mol. Biol. Cell. 22: 2270-2281.
Nakamura. K., Nemani, V.M., Azarbal, F., Skibinski, G., Levy, J.M., Egami, K., Munishkina, L., Zhang, J., Gardner, B., Wakabayashi, J., Sesaki, H., Cheng, Y., Finkbeiner, S., Nussbaum,.R.L., Masliah, E., and Edwards, R.H. (2011). Direct membrane association drives mitochondrial fission by the Parkinson Disease-associated protein ?-synuclein. J. Biol. Chem. 286: 20710-20726.
Tamura, Y., Iijima, M., and Sesaki, H. (2010). Mdm35p imports Ups proteins into the mitochondrial intermembrane space by functional complex formation. EMBO J. 29: 2875-2887.
Zhang, P., Wang, Y., Sesaki, H. and Iijima, M. (2010). Proteomic identification of PtdIns(3,4,5)P3-binding proteins in D. discoideum. Proc. Natl. Acad. Sci. USA. 107: 11829-11834.
Wakabayashi, J., Zhang, Z., Wakabayashi, N., Tamura, Y., Fukaya, M., Kensler, T.W., Iijima, M., and Sesaki, H. (2009). The dyanmin-related GTPase Drp1 is required for embryonic and brain development in mice. J. Cell Biol. 186: 805-816.T
Tamura, Y., Endo, T., Iijima, M., and Sesaki, H. (2009). Ups1p and Ups2p antagonistically regulate cardiolipin metabolism in mitochondria. J. Cell Biol. 185: 1029-1045.
Tamura, Y., Harada, Y., Shiota, T., Yamano, K., Watanabe, K., Yokota, M., Yamamoto, H., Sesaki, H., Endo, T. (2009). Tim23-Tim50 pair coordinates functions of translocators and motor proteins in mitochondrial protein import. J. Cell Biol. 184: 129-141.
Dunn, C.D., Tamura, Y., Sesaki, H., Jensen, R.E. (2008). Mgr3p and Mgr1p are adaptors for the mitochondrial i-AAA protease complex. Mol Biol Cell. 19: 5387-97.
Cerveny, K.L., Tamura, Y., Zhang, Z., Jensen, R.E., and Sesaki, H. (2007). Regulation of Mitochondrial Fusion and Division. Trend Cell Biol. 17:563-569.
Cerveny, K.L., Studer, S.L., Jensen, R.E., and Sesaki, H. (2007). Yeast mitochondrial division and distribution requires the cortical Num1 protein. Dev. Cell. 12:363-375.
Yoshino, R., Morio, T., Yamada, Y., Kuwayama, H., Sameshima, M., Tanaka, Y., Sesaki, H., and Iijima, M. (2007). Regulation of ammonia homeostasis by the ammonium transporter AmtA in Dictyostelium. Eukaryot Cell. 6: 2419-2428.
Jensen, R.E. and Sesaki, H. (2006). Ahead of the curve: mitochondrial fusion and phospholipase D. Nat. Cell Biol. 8: 1215-1217.
Sesaki, H., Dunn, C.D., Iijima, M., Shepard, K.A., Yaffe, M.P., Machamer, C.E., and Jensen, R.E. (2006). Ups1p, a conserved intermembrane space protein, regulates mitochondrial shape and alternative topogenesis of Mgm1p. J. Cell Biol. 173: 651-658.
Sesaki, H. and Jensen, R.E. (2004). Ugo1p links the Fzo1p and Mgm1p GTPases for mitochondrial fusion. J. Biol. Chem. 279: 28298-28303.
Jensen, R.E., Dunn, C., Youngman, M. and Sesaki, H. (2004). Mitochondrial building blocks. Trends Cell Biol. 12: 215-218.
Sesaki, H., Southard, S.M, Aiken Hobbs, A.E. and Jensen, R.E. (2003). Cells lacking Pcp1p/Ugo2p, a rhomboid-related protease required for Mgm1p processing, lose mtDNA and mitochondrial structure in a Dnm1p-dependent manner, but remain competent for mitochondrial fusion. Biochem. Biophys. Res. Commun. 308: 276-283.
Sesaki, H., Southard, S.M, Yaffe, M.P., and Jensen, R.E. (2003). Mgm1p, a dynamin-related GTPase, is essential for fusion of the mitochondrial outer membrane. Mol. Biol. Cell. 14: 2342-2356.
Sesaki, H. and Jensen, R.E. (2001). UGO1 encodes an outer membrane protein required for mitochondrial fusion. J. Cell Biol. 152:1123-34.
Jensen, R.E., Aiken Hobbs, A.E., Cerveny, K. and Sesaki, H. (2000). Yeast mitochondrial dynamics: fusion, division, segregation and shape. Microsc. Res. Tech. 51:573-583.
Sesaki, H. and Jensen, R.E. (1999). Division versus fusion: Dnm1p and Fzo1p antagonistically regulate mitochondrial shape. J. Cell Biol. 147: 699-706.