dorsomorphin and Reperfusion-Injury

Energy stress depletes ATP and induces cell death. Here we identify an unexpected inhibitory role of energy stress on ferroptosis, a form of regulated cell death induced by iron-dependent lipid peroxidation. We found that ferroptotic cell death and lipid peroxidation can be inhibited by treatments that induce or mimic energy stress. Inactivation of AMP-activated protein kinase (AMPK), a sensor of cellular energy status, largely abolishes the protective effects of energy stress on ferroptosis in vitro and on ferroptosis-associated renal ischaemia-reperfusion injury in vivo. Cancer cells with high basal AMPK activation are resistant to ferroptosis and AMPK inactivation sensitizes these cells to ferroptosis. Functional and lipidomic analyses further link AMPK regulation of ferroptosis to AMPK-mediated phosphorylation of acetyl-CoA carboxylase and polyunsaturated fatty acid biosynthesis. Our study demonstrates that energy stress inhibits ferroptosis partly through AMPK and reveals an unexpected coupling between ferroptosis and AMPK-mediated energy-stress signalling.

Topics: A549 Cells; Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Animals; Cell Line, Tumor; Cyclohexylamines; Embryo, Mammalian; Energy Metabolism; Fatty Acids, Unsaturated; Ferroptosis; Fibroblasts; Gene Expression Regulation; Glucose; Humans; Iron; Kidney; Lipid Peroxidation; MCF-7 Cells; Mice; Mice, Transgenic; Phenylenediamines; Phosphorylation; Piperazines; Primary Cell Culture; Pyrazoles; Pyrimidines; Reperfusion Injury; Signal Transduction; Stress, Physiological

Here, we have investigated the effect of metformin pretreatment in the rat models of global cerebral ischemia. Cerebral ischemia which leads to brain dysfunction is one of the main causes of neurodegeneration and death worldwide. Metformin is used in clinical drug therapy protocols of diabetes. It is suggested that metformin protects cells under hypoxia and ischemia in non-neuronal contexts. Protective effects of metformin may be modulated via activating the AMP activated protein kinase (AMPK). Our results showed that induction of 30 min global cerebral I/R injury using 4-vesseles occlusion model led to significant cell death in the rat brain. Metformin pretreatment (200 mg kg/once/day, p.o., 2 weeks) attenuated apoptotic cell death and induced mitochondrial biogenesis proteins in the ischemic rats, analyzed using histological and Western blot assays. Besides, inhibition of AMPK by compound c showed that metformin resulted in apoptosis attenuation via AMPK activation. Interestingly, AMPK activation was also involved in the induction of mitochondrial biogenesis proteins using metformin, inhibition of AMPK by compound c reversed such effect, further supporting the role of AMPK upstream of mitochondrial biogenesis proteins. In summary, Metformin pretreatment is able to modulate mitochondrial biogenesis and apoptotic cell death pathways through AMPK activation in the context of global cerebral ischemia, conducting the outcome towards neuroprotection.

Topics: Adenylate Kinase; Animals; Apoptosis; Brain; Brain Ischemia; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Activation; Hippocampus; Male; Metformin; Mitochondrial Turnover; Neuroprotective Agents; NF-E2-Related Factor 1; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Premedication; Pyrazoles; Pyrimidines; Rats; Reperfusion Injury; Signal Transduction; Transcription Factors