Metabolic stress exacerbates Parkinson’s disease pathology through mitochondrial dysfunction and ferroptosis

Epidemiological studies have linked type 2 diabetes to Parkinson's disease (PD), but causality and mechanisms remain unclear. Here, using Mendelian randomization, we identify genetically elevated 2‑hour post‑load glucose as a causal risk factor for PD. To investigate the underlying biology, we developed a mouse model combining glucose intolerance with MPTP‑induced dopaminergic injury. Glucose intolerance markedly exacerbated motor and cognitive deficits, dopaminergic neuron loss, and α‑synuclein accumulation. Mechanistically, hyperglycemia synergized with MPTP to impair mitochondrial respiration, collapse membrane potential, and disrupt cristae architecture. These changes were accompanied by iron overload, glutathione depletion, lipid peroxidation, downregulation of the ferroptosis suppressor GPX4, and upregulation of the pro‑ferroptosis enzyme ACSL4-a signature of ferroptosis. The same pathway was activated in human dopaminergic neurons exposed to high glucose and MPP⁺. Our findings establish that glucose intolerance directly aggravates PD pathology via mitochondrial dysfunction and ferroptosis, suggesting that targeting this cell death pathway or improving glycemic control could offer therapeutic opportunities for PD, especially in patients with metabolic comorbidities.