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.

Plasma-activated medium induces A549 cell injury via a spiral apoptotic cascade involving the mitochondrial–nuclear network

“…The mitochondrial pathway is one of the most important apoptosis signaling pathways in cells, and the Bcl 2 family is a key regulator of this pathway [28,49]. Bcl 2 functions as an anti-apoptotic factor in the outer mitochondrial membrane to maintain the integrity of the membrane, whereas Bax plays its pro-apoptotic role by disrupting the mitochondrial membrane.…”

Contribution of mitochondria and endoplasmic reticulum dysfunction in insulin resistance: Distinct or interrelated roles?

“…Because mitochondrial dysfunction has been associated with IR, palmitate-induced alterations of mitochondria may explain why reducing ER stress was not effective for improving insulin signalling in myotubes. Furthermore, recent data have suggested that mitochondrial DNA damage is upstream of palmitate-induced ER stress and autophagy in L6 skeletal muscle cells [61], and that palmitate-induced oxidative stress contributed to the loss of insulin-stimulated phoshorylation of PKB [60]. Moreover, palmitate can be incorporated in ER phospholipid membranes, leading to modifications of ER morphology [56] that could contribute to altered insulin sensitivity [51].…”

“…However, other studies point out that ER alterations are subsequent to mitochondrial dysfunction in metabolic diseases. For example, it was shown that changes in ER homoeostasis occurred via a mitochondria-dependent pathway in the liver of rats exposed to excessive inflammation [68] and in palmitatetreated L6 myotubes [61].…”

The roles of oxidative stress, endoplasmic reticulum stress, and autophagy in aldosterone/mineralocorticoid receptor-induced podocyte injury

“…16 Our previous study found that ROS contributed to aldosterone-induced podocyte injury. 17 Recently, oxidative stress has been shown to be an initiator and major contributor to both ER stress and autophagy, 18 although the underlying mechanisms responsible for these events are still unknown.…”