Energy stress activates AMPK to suppress ferroptosis in neurodegenerative proteinopathies
Ferroptosis, an iron-dependent and lipid peroxidation-driven form of regulated cell death, has emerged as a key contributor to neuronal degeneration in protein misfolding disorders. However, how cellular energy metabolism modulates ferroptotic susceptibility in neurodegenerative proteinopathies remains incompletely defined. The present study investigated whether the previously described energy stress-AMP-activated protein kinase (AMPK)-acetyl-CoA carboxylase (ACC) ferroptosis checkpoint operates in disease-relevant neuronal proteinopathy models. Pharmacological and genetic interventions, cell viability assays, lipid peroxidation measurements, western blotting, RNA interference, and behavioral analyses were performed in SH-SY5Y cells, transgenic Caenorhabditis elegans (C. elegans), and 3xTg-AD mice. In SH-SY5Y cells, glucose deprivation, 2-deoxy-D-glucose (2DG), or 5-aminoimidazole-4-carboxamide ribonucleoside reduced ferroptotic cell death induced by erastin or RSL3 and attenuated ferroptosis-associated neuronal injury induced by amyloid precursor protein, α-synuclein A53T, and polyQ74. This protection was associated with AMPK activation, ACC1 phosphorylation, reduced lipid peroxidation, sensitivity to ferroptosis inhibition, glutathione peroxidase 4 restoration, and acyl-CoA synthetase long-chain family member 4 suppression. AMPK inhibition or knockdown weakened the protection conferred by glucose deprivation, while aak-2 RNAi attenuated the protective effects of 2DG in C. elegans, supporting a substantial contribution of AMPK-ACC1-associated signaling to ferroptosis suppression under energy stress. Consistently, 2DG or liproxstatin-1 reduced ferroptosis-associated oxidative damage and improved behavioral or cognitive deficits in transgenic C. elegans and 3xTg-AD mice. These findings extend the established AMPK-ACC ferroptosis checkpoint to neurodegenerative proteinopathy models and support energy stress-associated AMPK-ACC1 signaling as an important metabolic defense mechanism against ferroptosis-related neuronal injury.