High-Glucose Stimulation Increases Reactive Oxygen Species Production Through the Calcium and Mitogen-Activated Protein Kinase-Mediated Activation of Mitochondrial Fission

Abstract

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.

Suppression of autophagy is protective in high glucose-induced cardiomyocyte injury

“…Autophagy has been thought to be a survival mechanism in response to various starvation and stress conditions, 23 and high glucose is well known to induce cardiomyocyte death, [7][8][9][10][11][12][13][14] raising the possibility that the inhibited autophagy may contribute to hyperglycemic toxicity. If this is true, restoring or enhancing autophagy would protect against high glucose-induced cardiomyocyte death, and conversely, inhibiting autophagy would predispose cardiomyocytes to high glucose injury.…”

“…[4][5][6] Indeed, the cardiotoxic effects of hyperglycemia have been corroborated in numerous in vitro and in vivo studies. High levels of glucose can directly induce cardiomyocyte death in culture, [7][8][9][10][11][12][13][14] which has been attributed to excessive production of reactive oxygen species (ROS) triggered by high glucose. The critical role of oxidative stress in mediating diabetic cardiac injury has been strongly supported by the ability of various antioxidants to prevent or slow the development of diabetic cardiomyopathy in animal studies.…”

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

“…We therefore postulate that the X protein may induce modifications of the activity of cellular kinases through mitochondriacytoplasm cross talk. Phosphorylation of Drp1 S616 is mediated by multiple kinases, including CDK1 during mitosis 35 , ERK1/2 under high glucose conditions 50 or PKCd during hypertension 51 .…”

Mitochondrial Morphology in Metabolic Diseases

“…The middle domain has been implicated in the oligomerization of DLP1 required for its membrane-constricting properties (22), and the CC domain interacts with the N-terminal domains to regulate the GTPase activity. These domains of the protein are the subject of multiple posttranslational modifications, including phosphorylation (21,31,61,132,151), S-nitrosylation (25), SUMOylation (11,51,62,139), and ubiquitylation (94,144), affecting DLP1 function, interactions, stability, and subcellular localization.…”