Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson's disease.

ABSTRACT: Mutations in the E3 ubiquitin ligase parkin are the most common cause of early-onset Parkinson's disease (PD). Although parkin modulates mitochondrial and endolysosomal homeostasis during cellular stress, whether parkin regulates mitochondrial and lysosomal cross-talk under physiologic conditions remains unresolved. Using transcriptomics, metabolomics and super-resolution microscopy, we identify amino acid metabolism as a disrupted pathway in iPSC-derived dopaminergic neurons from patients with parkin PD. Compared to isogenic controls, parkin mutant neurons exhibit decreased mitochondria-lysosome contacts via destabilization of active Rab7. Subcellular metabolomics in parkin mutant neurons reveals amino acid accumulation in lysosomes and their deficiency in mitochondria. Knockdown of the R

SUBMITTER: Peng W 

PROVIDER: S-EPMC10355824 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature