CHCHD2 mitigates age-associated proteostatic collapse by maintaining homeostasis of the mitochondria-lysosome axis

Abstract Mutations in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), including the Parkinson’s disease (PD)-linked CHCHD2 T61I mutation, are associated with Lewy body disorders (LBDs) by unknown mechanisms. Here, we demonstrate that CHCHD2 T61I exacerbates age-related brain pathologies, including axonal degeneration and cognitive deficits, by disrupting the mitochondria-lysosome axis. Specifically, CHCHD2 T61I binds and reduces cathepsin B (CTSB) and cathepsin L (CTSL) levels, inducing lysosomal membrane permeability and impairing α-synuclein fibril clearance. We also demonstrate that human CHCHD2 declines in the brain with age, while expression of wild-type CHCHD2 safeguards against age-related neuroinflammation, dopaminergic neuron loss, insoluble protein aggregation, and structural deterioration of mitochondria and lysosomes. These findings, supported by observed reductions in CTSB and CHCHD2 in human LBD brains, establish CHCHD2 as a key regulator of neuronal resilience to aging and proteostatic collapse via the mitochondria-lysosome axis. Preventing age-associated CHCHD2 decline offers a therapeutic strategy to preserve brain health throughout aging.