IDH2 deficiency increases the liver susceptibility to ischemia-reperfusion injury via increased mitochondrial oxidative injury.

Abstract

Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) is a major producer of mitochondrial NADPH, required for glutathione (GSH)-associated mitochondrial antioxidant systems including glutathione peroxidase (GPx) and glutathione reductase (GR). Here, we investigated the role of IDH2 in hepatic ischemia-reperfusion (HIR)-associated mitochondrial injury using Idh2-knockout (Idh2-/-) mice and wild-type (Idh2+/+) littermates. Mice were subjected to either 60min of partial liver ischemia or sham-operation. Some mice were administered with 2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (mito-TEMPO, a mitochondria-targeting antioxidant). HIR induced severe histological and functional damages of liver in both Idh2+/+ mice and Idh2-/- mice and those damages were more severe in Idh2-/- mice than in wild-type littermates. HIR induces dysfunction of IDH2, leading to the decreases of NADPH level and mitochondrial GR and GPx functions, consequently resulting in mitochondrial and cellular oxidative injury as reflected by mitochondrial cristae loss, mitochondrial fragmentation, shift in mitochondrial fission, cytochrome c release, and cell death. These HIR-induced changes were greater in Idh2-/- mice than wild-type mice. The mito-TEMPO supplement significantly attenuated the aforementioned changes, and these attenuations were much greater in Idh2-/- mice when compared with wild-type littermates. Taken together, results have demonstrated that HIR impairs in the IDH2-NADPH-GSH mitochondrial antioxidant system, resulting in increased mitochondrial oxidative damage and dysfunction, suggesting that IDH2 plays a critical role in mitochondrial redox balance and HIR-induced impairment of IDH2 function is associated with the pathogenesis of ischemia-reperfusion-induced liver failure.

• Authors: Sang Jun Han, Hong Seok Choi, Jee In Kim, Jeen-Woo Park, Kwon Moo Park
• Journal: Redox biology (Redox Biol) Vol. 14 Pg. 142-153 (04 2018) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 28938192 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antioxidants
• bcl-2-Associated X Protein
• NADP
• Cytochromes c
• Hydrogen Peroxide
• Isocitrate Dehydrogenase
• isocitrate dehydrogenase 2, mouse
• Catalase
• Glutathione Peroxidase
• Glutathione Reductase
• Glutathione

Topics

• Animals
• Antioxidants (metabolism)
• Apoptosis
• Catalase (metabolism)
• Cytochromes c (metabolism)
• Glutathione (metabolism)
• Glutathione Peroxidase (metabolism)
• Glutathione Reductase (metabolism)
• Hydrogen Peroxide (analysis, metabolism)
• Isocitrate Dehydrogenase (deficiency, genetics)
• Liver (metabolism, pathology)
• Male
• Mice
• Mice, Knockout
• Mitochondria (metabolism, physiology)
• NADP (metabolism)
• Oxidative Stress
• Reperfusion Injury (mortality, pathology, veterinary)
• Survival Rate
• bcl-2-Associated X Protein (metabolism)