High-glucose stimulation increases reactive oxygen species production through the calcium and mitogen-activated protein kinase-mediated activation of mitochondrial fission.
Increased production of reactive oxygen species (ROS) from mitochondria is the main cause of hyperglycemic complications. We previously showed that hyperglycemic conditions induce mitochondrial fragmentation that is causal for ROS overproduction. This study was to identify signaling components that induce mitochondrial fragmentation in high-glucose stimulation. We found that exposing cells to the high-glucose concentration evokes increases in cytosolic Ca(2+). Chelating Ca(2+) in the high-glucose medium prevented not only the Ca(2+) transient but also mitochondrial fragmentation and the ROS increase, indicating that the Ca(2+) influx across the plasma membrane is an upstream event governing mitochondrial fission and the ROS generation in high-glucose stimulation. We found that the high-glucose-induced Ca(2+) increase activates the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2). The Ca(2+) chelation prevented the ERK1/2 activation, and inhibition of the ERK1/2 phosphorylation decreased mitochondrial fragmentation as well as ROS levels in high-glucose stimulation. In addition, the level of the mitochondrial fission protein dynamin-like protein 1 in mitochondria increased in high-glucose incubation in a Ca(2+)-dependent manner. In vitro kinase assays showed that ERK1/2 is capable of phosphorylating dynamin-like protein 1. These results demonstrate that high-glucose stimulation induces the activation of mitochondrial fission via signals mediated by intracellular Ca(2+) and ERK1/2.
Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
Tianzheng
T
Yu
Bong Sook
BS
Jhun
Yisang
Y
Yoon
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D034281:Dynamins; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D008099:Liver / Q000166:cytology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020558:GTP Phosphohydrolases; C519851:Dnm1l protein, rat; D034281:Dynamins; D005947:Glucose; D002118:Calcium