Mitochondrial acetyl-CoA reprogramming by the SIRT3-ACSS2-OPA1 axis confers resistance to ferroptosis in Parkinson's disease.

ABSTRACT: Mitochondrial dysfunction and ferroptosis have emerged as pivotal contributors to dopaminergic (DA) neuron degeneration in Parkinson's disease (PD). Here, a previously unrecognized SIRT3-ACSS2-OPA1 axis that couples mitochondrial acetyl-CoA (Ac-CoA) metabolism to ferroptosis resistance is identified. Analysis of public human substantia nigra datasets reveals marked reduction in SIRT3 expression, which is further confirmed in 6-OHDA-induced PD models. To establish translational significance, analyses of serum and peripheral blood mononuclear cells (PBMCs) from PD patient cohort demonstrates decreased SIRT3 protein levels and deacetylase activity. Moreover, SIRT3 overexpression inhibits ferroptosis and mitochondrial fragmentation in neurons. Mechanistically, SIRT3 deacetylates and activates

SUBMITTER: Ding XS 

PROVIDER: S-EPMC12859196 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature