Mitochondrial dysfunction-mediated metabolic remodeling of TCA cycle promotes Parkinson's disease through inhibition of H3K4me3 demethylation.

ABSTRACT: Parkinson's disease (PD), a neurodegenerative disorder caused by complex factors, is usually associated to mitochondrial dysfunctions but the links between such disorder and PD remain object of research. Here, we report that impaired mitochondrial quality control (MQC) system is a molecular basis of the mitochondrial dysfunction in PD and that tricarboxylic acid cycle (TCA cycle) disorder is the main feature of such mitochondrial dysfunction. Multi-omics analysis revealed that MDH2, OGDHL and IDH3G enzymes are bottlenecks in the enzymatic reactions of the TCA cycle in PD. Mechanistically, the abnormal α-KG/fumarate ratio caused by the TCA cycle bottleneck inhibits histone H3K4me3 demethylation and further enhances the expression of alpha-synuclein (SNCA), which may promote PD at an early s

SUBMITTER: Zhang X 

PROVIDER: S-EPMC12307738 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature