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Hiromi Sesaki, Ph.D.

Hiromi Sesaki, Ph.D.

Academic Titles: 
Associate Professor
Position Title: 
Principal Investigator
410-502-6842 (Office)
410-955-4129 (Fax)

Department of Cell Biology
Johns Hopkins University School of Medicine
725 N. Wolfe Street, 119 Hunterian
Baltimore, MD 21205

Research Topic:  Mitochondrial Dynamics and Phospholipid Metabolism

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. 
 

 

Research Interest: 
Mitochondrial dynamics; membrane fusion and fission
Lab Members:
Namesort descending Classification Email Phone
Daisuke Murata, Ph.D. Postdoctoral Fellow dmurata1@jhmi.edu 410-502-6842
Kie Itoh, Ph.D. Postdoctoral Fellow kito5@jhmi.edu 410-502-6842
Tatsuya Yamada, Ph.D. Postdoctoral Fellow tyamada6@jhmi.edu 410-502-6842
Yoshihiro Adachi, Ph.D. Postdoctoral Fellow yadachi1@jhmi.edu 410-502-6842
Selected Publications:
Yang J-M,  Schiapparelli P,  Nguyen H-N, Igarashi A, Zhang Q, Abbadi S, Amzel LM, Sesaki H, Quinones-Hinojosa A and Iijima M. Characterization of PTEN mutations in brain cancer reveals that PTEN mono-ubiquitination promotes protein stability and nuclear localization. Oncogene. In press.
Manczak M, Kandimalla R, Fry D, Sesaki H, Reddy PH. Protective Effects of Reduced Dynamin-related Protein 1 Against Amyloid Beta-induced Mitochondrial Dysfunction and Synaptic Damage in Alzheimer's Disease. Hum Mol Genet. 2016 Sep 27. pii: ddw330. [Epub ahead of print]
Kandimalla R, Manczak M, Fry D, Suneetha Y, Sesaki H, Reddy PH. Reduced Dynamin-related Protein 1 Protects Against Phosphorylated Tau-induced Mitochondrial Dysfunction and Synaptic Damage in Alzheimer's Disease. Hum Mol Genet. 2016 Sep 15. pii: ddw312. [Epub ahead of print]
Kojima R, Kajiura S, Sesaki H, Endo T, Tamura Y. Identification of multi-copy suppressors for ER-mitochondria tethering proteins in Saccharomyces cerevisiae. FEBS Lett. 2016; Epub ahead of print.  
Yamada T, Adachi Y, Fukaya M, Iijima M, Sesaki H. Drp1 deficiency leads to Rip3-mediated necroptotic neurodegeneration. Am J Pathol. 2016; Epub ahead of print
Adachi Y, Itoh K, Yamada T, Cerveny KL, Suzuki TL, Macdonald P, Frohman MA, Ramachandran R, Iijima M, Sesaki H. Coincident phosphatidic acid interaction restrains Drp1 in mitochondrial division. Mol Cell. 2016;63:1034-43.
Xiong ZM, Choi J, Wang K, Zhang H, Tariq Z, Wu D, Ko E, LaDana, C, Sesaki H, Cao K. Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria. Aging Cell. 2016;15:279-290  
Zhang L, Trushin S, Christensen TA, Bachmeier BV, Gateno B, Schroeder A, Yao J, Itoh K, Sesaki H, Poon WW, Gylys KH, Patterson ER, Parisi JE, Diaz Brinton R, Salisbury JL, Trushina E. Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease. Sci Rep. 2016;6:18725
Senoo H, Cai H, Wang Y, Sesaki H, Iijima M. The novel racE binding protein GflB sharpens ras activity at the leading edge of migrating cells. Mol Biol Cell. 2016;27(10):1596-605.
Roy M, Itoh K, Iijima M, Sesaki H. Parkin suppresses Drp1-independent mitochondrial division. Biochem Biophys Res Commun. 2016;475(3):283-8.
Khacho M, Clark A, Svoboda DS, Azzi J, MacLaurin JG, Meghaizel C, Sesaki H, Lagace DC, Germain M, Harper M-E, Park DS, Slack RS. Mitochondrial dynamics impact stem cell identity and fate decisions by regulating a nuclear transcriptional program. Cell Stem Cell. 2016;Epub ahead of print.  
Buck MD, O'Sullivan D, Klein Geltink RI, Curtis JD, Chang CH, Sanin DE, Qiu J, Kretz O, Braas D, van der Windt GJ, Chen Q, Huang SC, O'Neill CM, Edelson BT, Pearce EJ, Sesaki H, Huber TB, Rambold AS, Pearce EL. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell. 2016;Epub ahead of print
Klionsky DJ et al. (~ 2000 authors). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12:1-222
Yamada T, Adachi Y, Iijima M, Sesaki H. Making a division apparatus on mitochondria. Trends Biochem Sci. 2016;41:209-210
Senoo H, Sesaki H, Iijima M. A GPCR handles bacterial sensing in chemotaxis and phagocytosis. Dev Cell. 2016;36:354-356.
Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, Lacas-Gervais S, Fragaki K, Berg-Alonso L, Kageyama Y, Serre V, Moore D, Verschueren A, Rouzier A, Le Ber I, Augé G, Cochaud C, Lespinasse F, N’Guyen K, Yu Wai Man P, Sesaki H, Pouget J, Paquis-Flucklingerm V. Reply: High prevalence of CHCHD10 mutations in patients with frontotemporal dementia from China. Brain. 2016;Epub ahead of print
Genin EC, Plutino M, Bannwarth S, Villa E, Cisneros-Barroso E, Roy M, Ortega-Vila B, Fragaki K, Lespinasse F, Pinero-Martos E, Augé G, Moore D, Burté F, Lacas-Gervais S, Kageyama Y, Itoh K, Yu-Wai-Man P, Sesaki H, Ricci JE, Vives-Bauza C, Paquis-Flucklinger V. CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis. EMBO Mol Med. 2015;8:58-72
Roy, M., Reddy, P.H., Iijima, M., and Sesaki, H. (2015). Mitochondrial division and fusion in metabolism. Curr. Opin. Cell Biol. 33:111-118
Serasinghe, M.N., Weider, S.Y., Renault, T.T., Elkholi, R., Asciolla, J.J., Yao, J.L., Jabado, O., Hoehn, K., Kageyama, Y., Sesaki, H., and Chipuk, J.E. (2015). Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors. Mol. Cell. 57: 521-536.
Li, S., Xu, S., Roelofs, B.A., Boyman, L., Lederer, J.W., Sesaki, H., and Karbowski, M. (2015). Transient assembly of F-actin on the outer mitochondrial membrane contributes to mitochondrial fission. J. Cell Biol. 208: 109-123. 
Kageyama, Y., Hoshijima, M., Seo, K., Bedja, D., Sysa-Shah, P., Andrabi, S., Chen, W., Höke, A., Dawson, V.L., Dawson, T.M., Gabrielson, K., Kass, D.A., Iijima, M., and Sesaki, H. (2014). Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain. EMBO J. 33: 2798-2813.
Berthet, A., Margolis, E.B., Zhang, J., Hsieh, I., Zhang, J., Hnasko, T.S., Ahmad, J., Edwards, R.H., Sesaki, H., Huang, E.J., and Nakamura K. (2014). Loss of mitochondrial fission depletes axonal mitochondria in midbrain dopamine neurons. J. Neurosci. 34: 14304-14317.
Zhang, Q., Tamura, Y., Roy, M., Adachi, Y., and Iijima, M., and Sesaki, H. (2014). Biogenesis and roles of phospholipids in mitochondrial fusion, division and mitophagy. Cell Mol. Life Sci. 71: 3767-3778.
Itoh, K., Tamura, Y., Iijima, M., and Sesaki H. (2013). Effects of Fcj1-Mos1 and mitochondrial division on aggregation of mitochondrial DNA nucleoids and organelle morphology. Mol. Biol. Cell. 24: 1842-1851
Tamura, Y., Harada, Y., Nishikawa, S., Yamano, K., Megumi, K., Shiota, T., Kuroda, T., Kuge, O., Sesaki, H., Imai, K., Tomii, K., and Endo, T. (2013). Tam41 is a novel CDP-diacylglycerol synthase for cardiolipin biosynthesis in mitochondria. Cell Metabolism. 17: 709-18.
Kageyama, Y., Zhang, Z., Roda, R., Fukaya, M., Wakabayashi, J., Wakabayashi, N., Kensler, T.W., Reddy, P.H., Iijima, M. and Sesaki, H. (2012). Mitochondrial division ensures the survival of postmitotic neurons by suppressing oxidative damage. J. Cell Biol. 197(4):535-51.
Tamura, Y., Onguka, O., Itoh, K., Endo, T., Iijima, M., Claypool, S.M., and Sesaki, H. (2012). Phosphatidylethanolamine biosynthesis in mitochondria: phosphatidylserine (PS) trafficking is independent of a PS decarboxylase and intermembrane space proteins, Ups1p and Ups2p.  J. Biol. Chem. 287:43961-43971
Tamura, Y., Onguka, O., Aiken Hobbs, A.E., Jensen, R.E., Iijima, M., Claypool, S.M., and Sesaki, H. (2012). Role for two conserved intermembrane space proteins, Ups1p and Up2p, in intra-mitochondrial phospholipid trafficking. J. Biol. Chem. 287(19):15205-15218.
Tamura, Y., Itoh, K. and Sesaki, H. (2011). SnapShot: Mitochondrial dynamics. Cell. 145:1158-11581e
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. 
Tamura, Y., Iijima, M., and Sesaki, H. Mdm35p imports Ups proteins into the mitochondrial intermembrane space by functional complex formation. EMBO J. (2010). 29: 2875-2887.
Wakabayashi, J., Zhang, Z., Wakabayashi, N., Tamura, Y., Fukaya, M., Kensler, T.W., Iijima, M., and Sesaki, H. (2009). The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice. J. Cell Biol. 186: 805-816
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
Cerveny, K.L., Studer, S.L., Jensen, R.E., and Sesaki, H. (2007). Yeast mitochondrial division and distribution requires the cortical Num1 protein. Developmental Cell. 12: 363-375.
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. (2001). UGO1 encodes an outer membrane protein required for mitochondrial fusion. J Cell Biol. 152:1123-34. 
Sesaki, H. and Jensen, R.E. (1999). Division versus fusion: Dnm1p and Fzo1p antagonistically regulate mitochondrial shape. J. Cell Biol. 147: 699-706.