title: Mitochondrial DNA damage via augmented oxidative stress regulates endoplasmic reticulum stress and autophagy: crosstalk, links and signaling.
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.
authors.affiliation: Department of Cell Biology and Neuroscience, College of Medicine, University of South Alabama, Mobile, Alabama, United States of America.
authors.forename: Larysa V
authors.initials: LV
authors.lastname: Yuzefovych
authors.affiliation: Department of Cell Biology and Neuroscience, College of Medicine, University of South Alabama, Mobile, Alabama, United States of America.
authors.forename: Susan P
authors.initials: SP
authors.lastname: LeDoux
authors.affiliation: Department of Cell Biology and Neuroscience, College of Medicine, University of South Alabama, Mobile, Alabama, United States of America.
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Wilson
authors.affiliation: Department of Cell Biology and Neuroscience, College of Medicine, University of South Alabama, Mobile, Alabama, United States of America.
authors.forename: Lyudmila I
authors.initials: LI
authors.lastname: Rachek
mesh_terms: D000818:Animals; D001343:Autophagy; D002460:Cell Line; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D008931:Mitochondria, Muscle / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D051381:Rats; D015398:Signal Transduction
chemical_list: D004272:DNA, Mitochondrial