Fis1 and Drp1 cooperate in mitochondrial homeostasis (756.8)

Defects in mitochondrial fission and fusion cause numerous human disorders yet how these defects affect mitochondrial function and contribute to disease is unknown. Mitochondrial fission requires the dynamin-related GTPase Drp1 and a lethal mutation (A395D) was reported in a neonate with microcephaly, abnormal brain development, optic atrophy, and lactic acidemia (Waterham et al., 2007, N. Engl. J. Med. 356, 1736-1741). Another Drp1 mutation (C446F) was reported to cause severe cardiomyopathy in mice (Ashrafian et al., 2010, PLoS Genet 6, e1001000). We are determining how these mutants affect mechanoenzyme activity and function. For A395D, we found impaired localization, recruitment, assembly, and GTP hydrolysis. For C446F, we found impaired GTP hydrolysis and assembly. Thus, these mutants impair higher order assembly of Drp1 at mitochondria, leading to decreased fission, elongated mitochondria, and altered cellular distribution of mitochondria. Curiously, these mutants show enhanced in vitro interactions...