Zinc-Mediated Lysosomal Destabilization Links Mitochondrial Damage to Neuronal Death in a Cellular MPP⁺ Model of Parkinson's Disease.

ABSTRACT: Dysregulation of autophagy and lysosomal function is central to Parkinson's disease (PD), yet the upstream mechanisms leading to lysosomal failure remain unclear. Across primary mouse cortical neurons, MT-3 deficient primary mouse astrocytes, human iPSC-derived midbrain dopaminergic neurons, and Rho⁰ CHO cells lacking mitochondrial respiration, we investigated how mitochondrial stress perturbs zinc (Zn²⁺) homeostasis and lysosomal integrity. We identify intracellular zinc as a critical mediator linking mitochondrial dysfunction to lysosomal membrane permeabilization (LMP) and neuronal death. Inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium (MPP⁺) elevated reactive oxygen species (ROS) and intracellular zinc, jointly driving LMP. Blocking

SUBMITTER: Lee HS 

PROVIDER: S-EPMC12862199 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature