Isocitrate Dehydrogenase 2 Deficiency Induces Endothelial Inflammation via p66sh-mediated Mitochondrial Oxidative Stress

Biochem Biophys Res Commun. 2018 Sep 10;503(3):1805-1811. doi: 10.1016/j.bbrc.2018.07.117. Epub 2018 Jul 30.

Abstract

Isocitrate dehydrogenase 2 (IDH2) is an essential enzyme in the mitochondrial antioxidant system, which produces nicotinamide adenine dinucleotide phosphate, and thereby defends against oxidative stress. We have shown that IDH2 downregulation results in mitochondrial dysfunction and reactive oxygen species (ROS) generation in mouse endothelial cells. The redox enzyme p66shc is a key factor in regulating the level of ROS in endothelial cells. In this study, we hypothesized that IDH2 knockdown-induced mitochondrial dysfunction stimulates endothelial inflammation, which might be regulated by p66shc-mediated oxidative stress. Our results showed that IDH2 downregulation led to mitochondrial dysfunction by decreasing the expression of mitochondrial oxidative phosphorylation complexes I, II, and IV, reducing oxygen consumption, and depolarizing mitochondrial membrane potential in human umbilical vein endothelial cells (HUVECs). The dysfunction not only increased mitochondrial ROS levels but also activated p66shc expression in HUVECs and IDH2 knockout mice. IDH2 deficiency increased intercellular adhesion molecule (ICAM)-1 expression and mRNA levels of pro-inflammatory cytokines (tumor necrosis factor [TNF]-α, and interleukin [IL]-1β) in HUVECs. The mRNA expression of ICAM-1 in endothelial cells and plasma levels of TNF-α and IL-1β were also markedly elevated in IDH2 knockout mice. However, p66shc knockdown rescued IDH2 deficiency-induced mitochondrial ROS levels, monocyte adhesion, ICAM-1, TNF-α, and IL-1β expression in HUVECs. These findings suggest that IDH2 deficiency induced endothelial inflammation via p66shc-mediated mitochondrial oxidative stress.

Keywords: Endothelial inflammation; IDH2; Mitochondrial dysfunction; p66shc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Endothelial Cells / metabolism*
  • Humans
  • Inflammation / metabolism*
  • Isocitrate Dehydrogenase / deficiency*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Oxidative Stress*

Substances

  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, mouse