Perturbation of Akt Signaling, Mitochondrial Potential, and ADP/ATP Ratio in Acidosis-Challenged Rat Cortical Astrocytes.
Cells switch to anaerobic glycolysis when there is a lack of oxygen during brain ischemia. Extracellular pH thus drops and such acidosis causes neuronal cell death. The fate of astrocytes, mechanical, and functional partners of neurons, in acidosis is less studied. In this report, we investigated the signaling in acidosis-challenged rat cortical astrocytes and whether these signals were related to mitochondrial dysfunction and cell death. Exposure to acidic pH (6.8, 6.0) caused Ca2+release and influx, p38 MAPK activation, and Akt inhibition. Mitochondrial membrane potential was hyperpolarized after astrocytes were exposed to acidic pH as soon as 1 h and lasted for 24 h. Such mitochondrial hyperpolarization was prevented by SC79 (an Akt activator) but not by SB203580 (a p38 inhibitor) nor by cytosolic Ca2+chelation by BAPTA, suggesting that only the perturbation in Akt signaling was causally related to mitochondrial hyperpolarization. SC79, SB203580, and BAPTA did not prevent acidic pH-induced cell death. Acidic pH suppressed ROS production, thus ruling out the role of ROS in cytotoxicity. Interestingly, pH 6.8 caused an increase in ADP/ATP ratio and apoptosis; pH 6.0 caused a further increase in ADP/ATP ratio and necrosis. Therefore, astrocyte cell death in acidosis did not result from mitochondrial potential collapse; in case of acidosis at pH 6.0, necrosis might partly result from mitochondrial hyperpolarization and subsequent suppressed ATP production. J. Cell. Biochem. 118: 1108-1117, 2017. © 2016 Wiley Periodicals, Inc.
Department of Anesthesiology, Chang Gung Memorial Hospital, Chiayi, Taiwan.|Chang Gung University of Science and Technology, Chiayi, Taiwan.
King-Chuen
KC
Wu
Department of Anesthesiology, China Medical University and Hospital, Taichung, Taiwan.|Department of Anesthesiology, The Qingdao University Yuhuangding Hospital, Yantai, Shandong, China.
Ka-Shun
KS
Cheng
Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan.
Yu-Wen
YW
Wang
Department of Pharmacology, China Medical University, Taichung, Taiwan.
Yuh-Fung
YF
Chen
Department of Anesthesiology, China Medical University and Hospital, Taichung, Taiwan.
Kar-Lok
KL
Wong
Department of Anesthesiology, China Medical University and Hospital, Taichung, Taiwan.
Tzu-Hui
TH
Su
Division of Cardiology, Department of Medicine, Taipei Medical University Wan Fang Hospital, Taipei, Taiwan.
Paul
P
Chan
Department of Physiology, China Medical University, Taichung, Taiwan.
Yuk-Man
YM
Leung
D000143:Acids / Q000633:toxicity*; D000244:Adenosine Diphosphate / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000143:Acids; D017382:Reactive Oxygen Species; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium
ACIDOSIS; AKT; ASTROCYTES; MITOCHONDRIA HYPERPOLARIZATION