title: MISC-1/OGC links mitochondrial metabolism, apoptosis and insulin secretion.
abstract: We identified MISC-1 (Mitochondrial Solute Carrier) as the C. elegans orthologue of mammalian OGC (2-oxoglutarate carrier). OGC was originally identified for its ability to transfer α-ketoglutarate across the inner mitochondrial membrane. However, we found that MISC-1 and OGC are not solely involved in metabolic control. Our data show that these orthologous proteins participate in phylogenetically conserved cellular processes, like control of mitochondrial morphology and induction of apoptosis. We show that MISC-1/OGC is required for proper mitochondrial fusion and fission events in both C. elegans and human cells. Transmission electron microscopy reveals that loss of MISC-1 results in a decreased number of mitochondrial cristae, which have a blebbed appearance. Furthermore, our pull-down experiments show that MISC-1 and OGC interact with the anti-apoptotic proteins CED-9 and Bcl-x(L), respectively, and with the pro-apoptotic protein ANT. Knock-down of misc-1 in C. elegans and OGC in mouse cells induces apoptosis through the caspase cascade. Genetic analysis suggests that MISC-1 controls apoptosis through the physiological pathway mediated by the LIN-35/Rb-like protein. We provide genetic and molecular evidence that absence of MISC-1 increases insulin secretion and enhances germline stem cell proliferation in C. elegans. Our study suggests that the mitochondrial metabolic protein MISC-1/OGC integrates metabolic, apoptotic and insulin secretion functions. We propose a novel mechanism by which mitochondria integrate metabolic and cell survival signals. Our data suggest that MISC-1/OGC functions by sensing the metabolic status of mitochondria and directly activate the apoptotic program when required. Our results suggest that controlling MISC-1/OGC function allows regulation of mitochondrial morphology and cell survival decisions by the metabolic needs of the cell.
authors: Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada. mgallo@msl.ubc.ca
authors: Marco
authors: M
authors: Gallo
authors: Donha
authors: D
authors: Park
authors: Dan S
authors: DS
authors: Luciani
authors: Katarzyna
authors: K
authors: Kida
authors: Ferdinando
authors: F
authors: Palmieri
authors: Oliver E
authors: OE
authors: Blacque
authors: James D
authors: JD
authors: Johnson
authors: Donald L
authors: DL
authors: Riddle
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D005854:Germ Cells / Q000166:cytology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007814:Larva / Q000166:cytology / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D027321:Anion Transport Proteins; D029742:Caenorhabditis elegans Proteins; D007328:Insulin; C559122:MISC-1 protein, C elegans; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; C021723:oxoglutarate translocator; D049452:Green Fluorescent Proteins