Stimulation of cholesterol biosynthesis in mitochondrial complex I-deficiency lowers reductive stress and improves motor function and survival in mice

The majority of cellular energy is produced by the mitochondrial oxidative phosphorylation (OXPHOS) system. Failure first OXPHOS enzyme complex, NADH:ubiquinone oxidoreductase or complex I (CI), associated with multiple signs and symptoms presenting at variable ages onset. There no approved drug treatment yet to slow reverse progression CI-deficient disorders. Here, we present a comprehensive human metabolic network model genetically characterized patient-derived fibroblasts. Model calculations predicted that increased cholesterol production, export, utilization can counterbalance surplus reducing equivalents in fibroblasts, as these pathways consume considerable amounts NAD(P)H. We show fibrates attenuated NAD(P)H levels improved fibroblast growth stimulating production via enhancement its efflux. In (Ndufs4?/?) mice, fibrate resulted prolonged survival motor function, which was accompanied an efflux from peritoneal macrophages. Our results shine new light on use compensatory biological dysfunction, may lead novel therapeutic interventions for diseases currently cure exists.