Energy Stress-Induced Neuroprotection Against Ferroptosis in Dopaminergic Neurons

Ferroptosis, an iron-dependent form of regulated necrosis, is implicated in the pathogenesis of Parkinson's disease (PD). We studied the influence of energy stress on ferroptosis in differentiated dopaminergic neurons (LUHMES). Glucose deprivation conferred protection against ferroptosis induced by erastin or arachidonic acid plus iron by reducing lipid peroxidation. Glucose withdrawal did not protect against RSL3-induced ferroptosis, suggesting that direct GPX4 inhibition cannot be reversed by metabolic modulation. The expression of ferroptosis markers ACSL4, GPX4, xCT, and TFRc remained unaltered during glucose deprivation. Inhibition of glycolysis using 2-deoxyglucose confirmed the role of energy stress in the regulation of ferroptosis. Activation of AMP-activated protein kinase (AMPK) by AICAR protected LUHMES cells from erastin-induced ferroptosis, even in the presence of glucose. Conversely, AMPK expression inhibition by siRNA re-sensitized cells to ferroptosis under glucose-free conditions. These findings suggest that glucose metabolism and AMPK-mediated energetic stress play crucial roles in regulating ferroptosis in dopaminergic neurons, with potential implications for understanding the mechanisms of neurodegeneration in PD. These findings identify a potential bioenergetic checkpoint regulating ferroptosis susceptibility under conditions of severe energy stress.