Mitochondrial fission and fusion require recruitment, assembly and disassembly of large protein complexes, but very few contributing proteins and their functions are known. Members of the dynamin family are key players: Drp1 is a cytosolic dynamin-related protein that mediates fission, Mitofusins are mitochondrial outer membrane dynamin-related proteins that mediate outer membrane fusion and Opa1 is an intermembrane space dynamin- related protein that mediates inner membrane fusion. We focus on the mechanisms involved in these processes and the cellular defects that arise when they are disrupted.
In Aim 1, we propose to investigate alternative pathways for mitochondrial fission in C. elegans. We discovered that mitochondria in gonads of C. elegans drp-1 null alleles have seemingly wildtype mitochondria, which suggests that fission can occur without Drp1. This novel pathway could be specific for germlines in higher eukaryotes. We will investigate the mechanisms of Drp1 independent fission using live cell imaging, genetics and biochemistry.
In Aim 2, we propose to investigate Mff function in mammalian cells. Mff is a novel tail-anchored protein required for mitochondrial fission in mammalian cells. Mff may affect Drp1 targeting to mitochondria or it may affect some other aspect of the scission process. We will investigate possible interactions between Mff, Drp1 and other mitochondrial fission proteins. These experiments will help determine the function of Mff and its place in the mitochondrial fission process.
In Aim 3, we propose to investigate inducible proteolysis of Opa1 in mammalian cells. Opa1 is subjected to complex proteolytic processing in mammals. Inducible proteolysis during apoptosis inactivates Opa1, which could facilitate the release of cytochrome c from mitochondria. New data from our lab suggests that inducible cleavage is mediated by a protease called Oma1. We will verify this and we will explore possible synergy with other mitochondrial proteases. These experiments will help elucidate a novel pathway for inducible proteolysis in mammals.
In Aim 4, we propose to investigate the mechanisms of Opa1 pathogenesis. We discovered that C. elegans Opa1 mutants are highly sensitive to damage from Reactive Oxygen Species (ROS). ROS also provides a plausible mechanism for pathogenesis in patients with dominant optic atrophy (a degenerative eye disease caused by mutations in Opa1). We will test this and alternative hypotheses for pathogenesis (faulty segregation of mtDNA or a direct role in apoptosis). We will also determine whether components of the electron transport chain produce more ROS in C. elegans Opa1 mutants. These experiments will help determine the relevance of ROS for optic atrophy and begin to address the underlying mechanisms of pathogenesis. Together our experiments will broaden our knowledge of mitochondrial fission and fusion, and provide new avenues for treatments of mitochondrial diseases.

Public Health Relevance

Mitochondria are the power plants in cells. These small compartments frequently divide and fuse with each other. Mitochondrial fission and fusion play critical roles in many diseases, ranging from cancer to peripheral neuropathies and blindness, but the mechanisms underlying these processes are poorly understood. We focus on finding and analyzing new proteins that contribute to these processes, thus laying a foundation for research applied to human disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cell Structure and Function (CSF)
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Ainsztein, Alexandra M
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University of California Los Angeles
Schools of Medicine
Los Angeles
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Shen, Qinfang; Yamano, Koji; Head, Brian P et al. (2014) Mutations in Fis1 disrupt orderly disposal of defective mitochondria. Mol Biol Cell 25:145-59
Wexler-Cohen, Yael; Stevens, Grant C; Barnoy, Eran et al. (2014) A dynamin-related protein contributes to Trichomonas vaginalis hydrogenosomal fission. FASEB J 28:1113-21
Fares, Hanna; van der Bliek, Alexander M (2012) Analysis of membrane-bound organelles. Methods Cell Biol 107:239-63
Head, Brian P; Zulaika, Miren; Ryazantsev, Sergey et al. (2011) A novel mitochondrial outer membrane protein, MOMA-1, that affects cristae morphology in Caenorhabditis elegans. Mol Biol Cell 22:831-41
Head, Brian; Griparic, Lorena; Amiri, Mandana et al. (2009) Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. J Cell Biol 187:959-66
Kanazawa, Takayuki; Zappaterra, Mauro D; Hasegawa, Ayako et al. (2008) The C. elegans Opa1 homologue EAT-3 is essential for resistance to free radicals. PLoS Genet 4:e1000022
Gandre-Babbe, Shilpa; van der Bliek, Alexander M (2008) The novel tail-anchored membrane protein Mff controls mitochondrial and peroxisomal fission in mammalian cells. Mol Biol Cell 19:2402-12
Griparic, Lorena; Kanazawa, Takayuki; van der Bliek, Alexander M (2007) Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J Cell Biol 178:757-64
Hasegawa, Ayako; van der Bliek, Alexander M (2007) Inverse correlation between expression of the Wolfs Hirschhorn candidate gene Letm1 and mitochondrial volume in C. elegans and in mammalian cells. Hum Mol Genet 16:2061-71
Gandre, Shilpa; van der Bliek, Alexander M (2007) Mitochondrial division in Caenorhabditis elegans. Methods Mol Biol 372:485-501

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