Dose-dependent CHCHD10 dysregulation affects motor neuron disease severity and creatine metabolism

Dominant defects in CHCHD10, a mitochondrial intermembrane space protein, lead to a range of neurological and muscle phenotypes including amyotrophic lateral sclerosis. Many patients present with spinal muscular atrophy Jokela type (SMAJ), which is caused by a heterozygous p.G66V variant. While most disease variants lead to aggregation of CHCHD10 and activation of proteotoxic stress responses, the pathogenic mechanisms of the p.G66V variant have been less investigated. We report here the first homozygous CHCHD10 patient, with variant p.G66V. We compare the metabolic findings in heterozygous and homozygous SMAJ patient skin fibroblasts, and in motor neurons differentiated from patient-specific stem cells as well as a novel mouse model of SMAJ. Our findings show that p.G66V variant leads to dose-depended reduction of the CHCHD10 protein in a cell type specific manner. In addition, CHCHD10 p.G66V dysregulates energy metabolism, leading to altered redox balance and energy buffering by creatine metabolism.