CHCHD2 Mutant Mice Link Mitochondrial Deficits to PD Pathophysiology
Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD), but the mechanisms by which it drives autosomal dominant and idiopathic forms of PD remain unclear. To investigate this, we generated and performed a comprehensive phenotypic analysis of a knock-in mouse model carrying the T61I mutation in the mitochondrial protein CHCHD2, which causes late-onset symptoms indistinguishable from idiopathic PD. We observed pronounced mitochondrial disruption in substantia nigra (SN) dopaminergic neurons, including distorted ultrastructure and CHCHD2 aggregation, as well as disrupted mitochondrial protein-protein interactions in brain lysates. These abnormalities were associated with a whole-body metabolic shift towards glycolysis, elevated mitochondrial ROS, and progressive accumulation of aggregated a-synuclein. In idiopathic PD, CHCHD2 gene expression also correlated with a-synuclein levels in vulnerable dopaminergic neurons, and CHCHD2 protein accumulated in early Lewy aggregates. These findings delineate a pathogenic cascade in which CHCHD2 accumulation impairs mitochondrial respiration and increases ROS production, driving a-synuclein aggregation and neurodegeneration. Overall design: Midbrain sections from 16-month-old CHCHD2 T61I mutant mice (n = 8) and 13-month-old CHCHD2 knockout mice (n = 4), along with their respective littermate controls, were analyzed in this study.