High-glucose stimulation increases reactive oxygen species production through the calcium and mitogen-activated protein kinase-mediated activation of mitochondrial fission

Tianzheng Yu, Bong Sook Jhun, Yisang Yoon

Research output: Contribution to journalArticle

141 Citations (Scopus)

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 Ca2+ in the high-glucose medium prevented not only the Ca2+ transient but also mitochondrial fragmentation and the ROS increase, indicating that the Ca2+ 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 Ca2+ increase activates the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2). The Ca2+ 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 Ca2+-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 Ca2+ and ERK1/2.

Original languageEnglish (US)
Pages (from-to)425-437
Number of pages13
JournalAntioxidants and Redox Signaling
Volume14
Issue number3
DOIs
StatePublished - Feb 1 2011

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Mitochondrial Dynamics
Mitogen-Activated Protein Kinases
Reactive Oxygen Species
Chemical activation
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Calcium
Glucose
Dynamins
Mitochondria
Chelation
Phosphorylation
Proteins
Mitochondrial Proteins
Cell membranes
Assays
Phosphotransferases
Cell Membrane

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry

Cite this

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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 Ca2+ in the high-glucose medium prevented not only the Ca2+ transient but also mitochondrial fragmentation and the ROS increase, indicating that the Ca2+ 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 Ca2+ increase activates the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2). The Ca2+ 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 Ca2+-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 Ca2+ and ERK1/2.",
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