Mitochondrial DNA Damage via Augmented Oxidative Stress Regulates Endoplasmic Reticulum Stress and Autophagy: Crosstalk, Links and Signaling

Larysa V Yuzefovych,Glenn L Wilson,Susan P Ledoux,Lyudmila I Rachek,Yidong Bai

doi:10.1371/journal.pone.0083349

Larysa V Yuzefovych, Glenn L Wilson + Show 3 more

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https://doi.org/10.1371/journal.pone.0083349

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Journal: PloS one	Publication Date: Dec 13, 2013
Citations: 77	License type: CC BY 4.0

Affiliation: University of South Alabama

Abstract

Saturated free fatty acids (FFAs) have been implicated in the increase of oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, autophagy, and insulin resistance (IR) observed in skeletal muscle. Previously, we have shown that palmitate-induced mitochondrial DNA (mtDNA) damage triggers mitochondrial dysfunction, mitochondrial reactive oxygen species (mtROS) production, apoptosis and IR in L6 myotubes. The present study showed that mitochondrial overexpression of human 8-oxoguanine DNA glycosylase/AP lyase (hOGG1) decreased palmitate-induced carbonylation of proteins in mitochondria. Additionally, we found that protection of mtDNA from palmitate-induced damage significantly diminished markers of both ER stress and autophagy in L6 myotubes. Moreover, we observed that the addition of ROS scavenger, N-acetylcystein (NAC), to palmitate diminished both ER stress and autophagy markers mimicking the effect of mitochondrial overexpression of hOGG1. This is the first study to show that mtDNA damage is upstream of palmitate-induced ER stress and autophagy in skeletal muscle cells.

Highlights

Increasing evidence, accumulated over the last decade, indicates that mitochondrial dysfunction and oxidative stress are important components contributing to the development of insulin resistance (IR) in skeletal muscle [1,2,3], but the underlying mechanisms responsible for these events are still unknown
Since mitochondrial dysfunction [1,3], endoplasmic reticulum (ER) stress [6,7] and dysregulated autophagy [8,9] all contribute to the development of IR, this study sheds new light on the cause-effect relationships and sequence of events leading to IR, indicating that mitochondrial DNA (mtDNA) damage is an early step in the chain of pathological events leading to IR
We sought to evaluate whether palmitate induced ER stress in skeletal muscle cells, since the activation of ER stress and its contribution to the development of IR in skeletal muscle/ skeletal muscle cell has been debated, with some studies showing that palmitate [12] and high fat diet [5,7] induced ER stress in mouse skeletal muscle, whereas other failed to show activation of ER stress markers in skeletal muscle of obese mice [6], as well as of insulin resistant patients [13]

Summary

Introduction

Increasing evidence, accumulated over the last decade, indicates that mitochondrial dysfunction and oxidative stress are important components contributing to the development of IR in skeletal muscle [1,2,3], but the underlying mechanisms responsible for these events are still unknown. Since we have recently shown that IR in skeletal muscle was associated with increased markers of both autophagy and endoplasmic reticulum (ER) stress [5], this study was designed to further evaluate the role of mtDNA damage in these processes. Since mitochondrial dysfunction [1,3], ER stress [6,7] and dysregulated autophagy [8,9] all contribute to the development of IR, this study sheds new light on the cause-effect relationships and sequence of events leading to IR, indicating that mtDNA damage is an early step in the chain of pathological events leading to IR

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