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misc-1/OGC is a new stress response gene and regulator of apoptosis, germline stem cell proliferation and insulin secretion Gallo, Marco

Abstract

The present work produced new insights on the function of an ascaroside molecule and a gene that affect formation of dauer larvae, a diapause stage in Caenorhabditis elegans. Our results indicate that the ascaroside daumone, although a component of the dauer pheromone, does not act through signalling pathways active in the cilia. Furthermore, daumone has toxic effects if the animals are exposed to dauer-inducing concentrations of the compound. This ascaroside is not able, by itself, to recapitulate the full spectrum of events that occur during dauer formation. We identified misc-1 (MItochondrial Solute Carrier) as a novel suppressor of the dauer phenotype of daf-2/IGF1R mutants. We provide evidence that MISC-1 is the putative orthologue of mammalian OGC (2-OxoGlutarate Carrier), a metabolic carrier of the inner mitochondrial membrane. We show that a misc-1 null allele suppresses the dauer phenotype of daf-2 mutants by increasing insulin secretion. Consistent with this result, misc-1 mutants have increased proliferation of germline stem cells. Furthermore, we show that MISC-1 and OGC are involved in a phylogenetically conserved apoptosis pathway. Reduced levels of MISC-1 in C. elegans and OGC in human cells result in mitochondrial fragmentation. MISC-1 and human OGC physically interact with the anti-apoptotic Bcl-2-family members CED-9 and Bcl-xL, respectively, and are novel components of the mitochondrial permeability transition pore. Decreased levels of MISC-1 and OGC induce apoptosis in C. elegans and mouse cells. Finally, our experiments confirm that MISC-1/OGC has Reactive Oxygen Species (ROS)-detoxifying functions in vivo. We use misc-1 mutants to show that increased levels of ROS do not have negative effects on life span, contrary to current theories of aging. Using misc-1 mutants as a model, we show that extended life span of some C. elegans mitochondrial mutants is dependent on upregulation of extra-mitochondrial pathways of energy production. In conclusion, we show that the metabolic protein MISC-1/OGC affects insulin secretion, mitochondrial dynamics, apoptosis and ROS detoxification. We propose that MISC-1/OGC integrates metabolic and cell survival decisions by its physical interaction with the apoptotic machinery.

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