Multiomics study ofCHCHD10^S59L-related disease reveals energy metabolism downregulation: OXPHOS and β-oxidation deficiencies associated with lipids alterations

AbstractMutations in the coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) gene have been associated with a large clinical spectrum including myopathy, cardiomyopathy and amyotrophic lateral sclerosis (ALS). Herein, we analyzed the metabolic changes induced by the p.S59LCHCHD10mutation to identify new therapeutic opportunities. Using metabolomic, lipidomic and proteomic analysis we observed a strong alteration of metabolism in plasma and heart ofChchd10S59L/+mice compared to their wild type littermates at pre-symptomatic and symptomatic stages. In plasma, levels of phospholipids were decreased while those of carnitine derivatives and most of amino acids were increased. The cardiac tissue fromChchd10S59L/+mice showed a decreased Oxidative Phosphorylation (OXPHOS) and β-oxidation proteins levels as well as tricarboxylic acid cycle (TCA) intermediates and carnitine pathway metabolism. In parallel, lipidomics analysis reveals a drastic change in the lipidome, including triglycerides, cardiolipin and phospholipids. Consistent with this energetic deficiency in cardiac tissue, we show that L-acetylcarnitine supplementation improves the mitochondrial network length in IPS-derived cardiomyocytes from a patient carrying theCHCHD10S59L/+mutation. These data indicate that a bioenergetic intermediate such as L-acetylcarnitine may restore mitochondrial function inCHCHD10-related disease, due to the reduction in energy deficit that could be compensated by carnitine metabolic pathways.