Faculty Collaboration Database

Peroxynitrite nitrates adenine nucleotide translocase and voltage-dependent anion channel 1 and alters their interactions and association with hexokinase II in mitochondria. Mitochondrion 2019 May;46:380-392

Date

11/06/2018

Pubmed ID

30391711

Pubmed Central ID

PMC6487210

DOI

10.1016/j.mito.2018.10.002

Scopus ID

2-s2.0-85056228802 (requires institutional sign-in at Scopus site)   24 Citations

Abstract

Cardiac ischemia and reperfusion (IR) injury induces excessive emission of deleterious reactive O₂ and N₂ species (ROS/RNS), including the non-radical oxidant peroxynitrite (ONOO^-) that can cause mitochondria dysfunction and cell death. In this study, we explored whether IR injury in isolated hearts induces tyrosine nitration of adenine nucleotide translocase (ANT) and alters its interaction with the voltage-dependent anion channel 1 (VDAC1). We found that IR injury induced tyrosine nitration of ANT and that exposure of isolated cardiac mitochondria to ONOO^- induced ANT tyrosine, Y⁸¹, nitration. The exposure of isolated cardiac mitochondria to ONOO^- also led ANT to form high molecular weight proteins and dissociation of ANT from VDAC1. We found that IR injury in isolated hearts, hypoxic injury in H9c2 cells, and ONOO^- treatment of H9c2 cells and isolated mitochondria, each decreased mitochondrial bound-hexokinase II (HK II), which suggests that ONOO^- caused HK II to dissociate from mitochondria. Moreover, we found that mitochondria exposed to ONOO^- induced VDAC1 oligomerization which may decrease its binding with HK II. We have reported that ONOO^- produced during cardiac IR injury induced tyrosine nitration of VDAC1, which resulted in conformational changes of the protein and increased channel conductance associated with compromised cardiac function on reperfusion. Thus, our results imply that ONOO^- produced during IR injury and hypoxic stress impeded HK II association with VDAC1. ONOO^- exposure nitrated mitochondrial proteins and also led to cytochrome c (cyt c) release from mitochondria. In addition, in isolated mitochondria exposed to ONOO^- or obtained after IR, there was significant compromise in mitochondrial respiration and delayed repolarization of membrane potential during oxidative (ADP) phosphorylation. Taken together, ONOO^- produced during cardiac IR injury can nitrate tyrosine residues of two key mitochondrial membrane proteins involved in bioenergetics and energy transfer to contribute to mitochondrial and cellular dysfunction.

Author List

Yang M, Xu Y, Heisner JS, Sun J, Stowe DF, Kwok WM, Camara AKS

Authors

Amadou K. Camara PhD Professor in the Anesthesiology department at Medical College of Wisconsin
Wai-Meng Kwok PhD Professor in the Anesthesiology department at Medical College of Wisconsin
David F. Stowe MD, PhD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Line
Disease Models, Animal
Guinea Pigs
Hexokinase
Mitochondria
Mitochondrial ADP, ATP Translocases
Myocardium
Peroxynitrous Acid
Protein Binding
Protein Processing, Post-Translational
Rats
Reperfusion Injury
Voltage-Dependent Anion Channel 1