title: Vimar Is a Novel Regulator of Mitochondrial Fission through Miro.
abstract: As fundamental processes in mitochondrial dynamics, mitochondrial fusion, fission and transport are regulated by several core components, including Miro. As an atypical Rho-like small GTPase with high molecular mass, the exchange of GDP/GTP in Miro may require assistance from a guanine nucleotide exchange factor (GEF). However, the GEF for Miro has not been identified. While studying mitochondrial morphology in Drosophila, we incidentally observed that the loss of vimar, a gene encoding an atypical GEF, enhanced mitochondrial fission under normal physiological conditions. Because Vimar could co-immunoprecipitate with Miro in vitro, we speculated that Vimar might be the GEF of Miro. In support of this hypothesis, a loss-of-function (LOF) vimar mutant rescued mitochondrial enlargement induced by a gain-of-function (GOF) Miro transgene; whereas a GOF vimar transgene enhanced Miro function. In addition, vimar lost its effect under the expression of a constitutively GTP-bound or GDP-bound Miro mutant background. These results indicate a genetic dependence of vimar on Miro. Moreover, we found that mitochondrial fission played a functional role in high-calcium induced necrosis, and a LOF vimar mutant rescued the mitochondrial fission defect and cell death. This result can also be explained by vimar's function through Miro, because Miro's effect on mitochondrial morphology is altered upon binding with calcium. In addition, a PINK1 mutant, which induced mitochondrial enlargement and had been considered as a Drosophila model of Parkinson's disease (PD), caused fly muscle defects, and the loss of vimar could rescue these defects. Furthermore, we found that the mammalian homolog of Vimar, RAP1GDS1, played a similar role in regulating mitochondrial morphology, suggesting a functional conservation of this GEF member. The Miro/Vimar complex may be a promising drug target for diseases in which mitochondrial fission and fusion are dysfunctional.
authors.affiliation: State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China.|Aging and Disease lab of Xuanwu Hospital and Beijing Institute for Brain Disorders, Capital Medical University, Youanmen, Beijing, China.
authors.forename: Lianggong
authors.initials: L
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China.|Aging and Disease lab of Xuanwu Hospital and Beijing Institute for Brain Disorders, Capital Medical University, Youanmen, Beijing, China.
authors.forename: Ye
authors.identifier: http://orcid.org/0000-0002-7432-4038
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Aging and Disease lab of Xuanwu Hospital and Beijing Institute for Brain Disorders, Capital Medical University, Youanmen, Beijing, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Han
authors.affiliation: Aging and Disease lab of Xuanwu Hospital and Beijing Institute for Brain Disorders, Capital Medical University, Youanmen, Beijing, China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Aging and Disease lab of Xuanwu Hospital and Beijing Institute for Brain Disorders, Capital Medical University, Youanmen, Beijing, China.
authors.forename: Xunming
authors.initials: X
authors.lastname: Ji
authors.affiliation: Aging and Disease lab of Xuanwu Hospital and Beijing Institute for Brain Disorders, Capital Medical University, Youanmen, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
mesh_terms: D000818:Animals; D051186:Armadillo Domain Proteins / Q000235:genetics* / Q000378:metabolism; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002522:Chlorocebus aethiops; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000235:genetics*; D009336:Necrosis / Q000235:genetics / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D034622:RNA Interference; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051186:Armadillo Domain Proteins; D029721:Drosophila Proteins; D020662:Guanine Nucleotide Exchange Factors; C115955:RAP1GDS1 protein, human; C113448:vimar protein, Drosophila; C504427:Miro protein, Drosophila; D020741:rho GTP-Binding Proteins; D002118:Calcium