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

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 acetyl-CoA synthetase 2 (ACSS2), thereby facilitating the redistribution of Ac-CoA from mitochondria to the nucleus, leading to Optic atrophy 1 (OPA1) deacetylation. Meanwhile, this Ac-CoA reprogramming enhances histone H3K27 acetylation at the OPA1 promoter, and thereby drives OPA1 transcriptional upregulation. OPA1 restores mitochondrial homeostasis, alleviates iron accumulation, reduces lipid peroxidation, and ultimately suppresses ferroptosis. In vivo, pharmacological activation of SIRT3 or AAV-mediated Opa1 overexpression mitigates ferroptosis, preserves DA neurons, and improves motor performance in PD mice. This study uncovers mitochondrial Ac-CoA reprogramming as a key defense mechanism against ferroptosis, positioning the SIRT3–ACSS2–OPA1 pathway as a promising therapeutic target for PD. • SIRT3 expression and activity are decreased in Parkinson’s disease. • SIRT3 deacetylates ACSS2 to reprogram acetyl-CoA in Parkinson’s disease. • Acetyl-CoA reprogramming activates OPA1 to resist mitochondrial ferroptosis. • OPA1 restores disrupted mitochondrial homeostasis in Parkinson’s disease. • Both a SIRT3 activator and Opa1 overexpression alleviate parkinsonism in mice.