Energy stress modulation of AMPK/FoxO3 signaling inhibits mitochondria-associated ferroptosis
Sufang Zhong,
Wenjin Chen,
Bocheng Wang,
Chao Gao,
Xiamin Liu,
Yonggui Song,
Hui Qi,
Hongbing Liu,
Tao Wu,
Rikang Wang,
Baodong Chen
Affiliations
Sufang Zhong
Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China; Jiangxi University of Traditional Chinese Medicine, Nanchang, China
Wenjin Chen
Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China; Jiangxi University of Traditional Chinese Medicine, Nanchang, China
Bocheng Wang
Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China; Jiangxi University of Traditional Chinese Medicine, Nanchang, China
Chao Gao
Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China; Jiangxi University of Traditional Chinese Medicine, Nanchang, China
Xiamin Liu
Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China; Jiangxi University of Traditional Chinese Medicine, Nanchang, China
Yonggui Song
Key Laboratory of Evaluation of Traditional Chinese Medicine Efficacy (Prevention and Treatment of Brain Disease with Mental Disorders); Key Laboratory of Depression Animal Model Based on TCM Syndrome, Jiangxi Administration of Traditional Chinese Medicine; Key Laboratory of TCM for Prevention and Treatment of Brain Diseases with Cognitive Dysfunction, Jiangxi University of Chinese Medicine, Nanchang, China
Hui Qi
Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China; Jiangxi University of Traditional Chinese Medicine, Nanchang, China
Hongbing Liu
Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China; Jiangxi University of Traditional Chinese Medicine, Nanchang, China
Tao Wu
Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China; Jiangxi University of Traditional Chinese Medicine, Nanchang, China; Corresponding author. Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China.
Rikang Wang
Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China; Jiangxi University of Traditional Chinese Medicine, Nanchang, China; Corresponding author. Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China.
Baodong Chen
Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China; Jiangxi University of Traditional Chinese Medicine, Nanchang, China; Corresponding author. Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China.
Cancer cells and ischemic diseases exhibit unique metabolic responses and adaptations to energy stress. Forkhead box O 3a (FoxO3a) is a transcription factor that plays an important role in cell metabolism, mitochondrial dysfunction and oxidative stress response. Although the AMP-activated protein kinase (AMPK)/FoxO3a signaling pathway plays a pivotal role in maintaining energy homeostasis under conditions of energy stress, the role of AMPK/FoxO3a signaling in mitochondria-associated ferroptosis has not yet been fully elucidated. We show that glucose starvation induced AMPK/FoxO3a activation and inhibited ferroptosis induced by erastin. Inhibition of AMPK or loss of FoxO3a in cancer cells under the glucose starvation condition can sensitize these cells to ferroptosis. Glucose deprivation inhibited mitochondria-related gene expression, reduced mitochondrial DNA(mtDNA) copy number, decreased expression of mitochondrial proteins and lowered the levels of respiratory complexes by inducing FoxO3a. Loss of FoxO3a promoted mitochondrial membrane potential hyperpolarization, oxygen consumption, lipid peroxide accumulation and abolished the protective effects of energy stress on ferroptosis in vitro. In addition, we identified a FDA-approved antipsychotic agent, the potent FoxO3a agonist trifluoperazine, which largely reduced ferroptosis-associated cerebral ischemia-reperfusion (CIR) injuries in rats through AMPK/FoxO3a/HIF-1α signaling and mitochondria-dependent mechanisms. We found that FoxO3a binds to the promoters of SLC7A11 and reduces CIR-mediated glutamate excitotoxicity through inhibiting the expression of SLC7A11. Collectively, these results suggest that energy stress modulation of AMPK/FoxO3a signaling regulates mitochondrial activity and alters the ferroptosis response. The regulation of FoxO3a by AMPK may play a crucial role in mitochondrial gene expression that controls energy balance and confers resistance to mitochondria-associated ferroptosis and CIR injuries.
