Oxidative damage to mitochondrial DNA and glutathione oxidation in apoptosis: studiesin vivoandin vitro

Abstract

Free radicals may be involved in apoptosis although this is the subject of some controversy. Furthermore, the source of free radicals in apoptotic cells is not certain. The aim of this study was to elucidate the role of oxidative stress in the induction of apoptosis in serum-deprived fibroblast cultures and in weaned lactating mammary glands as in vitro and in vivo experimental models, respectively. Oxidative damage to mtDNA is higher in apoptotic cells than in controls. Oxidized glutathione (GSSG) levels in mitochondria from lactating mammary gland are also higher in apoptosis. There is a direct relationship between mtDNA damage and the GSSG/reduced glutathione (GSH) ratio. Furthermore, whole cell GSH is decreased and GSSG is increased in both models of apoptosis. Glutathione oxidation precedes nuclear DNA fragmentation. These signs of oxidative stress are caused, at least in part, by an increase in peroxide production by mitochondria from apoptotic cells. We report a direct relationship between glutathione oxidation and mtDNA damage in apoptosis. Our results support the role of mitochondrial oxidative stress in the induction of apoptosis.

Oxidative stress and regulation of glutathione in lung inflammation

“…This depletion by TNF-a is thought to be due to oxidative stress from mitochondrial leakage of O 2 . ± via the electron transport chain [143,221]. Oxidation of GSH is associated with activation of NF-kB and damage to mitochondrial DNA leading to apoptosis in fibroblasts in vitro and a decline in lung function in smokers [219,221,222].…”

“…± via the electron transport chain [143,221]. Oxidation of GSH is associated with activation of NF-kB and damage to mitochondrial DNA leading to apoptosis in fibroblasts in vitro and a decline in lung function in smokers [219,221,222]. It is likely that mitochondrial GSH plays a key role in maintaining cellular antioxidant defence systems, and thus cell integrity and function, under various conditions of oxidative stress [221,223].…”

“…Oxidation of GSH is associated with activation of NF-kB and damage to mitochondrial DNA leading to apoptosis in fibroblasts in vitro and a decline in lung function in smokers [219,221,222]. It is likely that mitochondrial GSH plays a key role in maintaining cellular antioxidant defence systems, and thus cell integrity and function, under various conditions of oxidative stress [221,223]. CHEN et al [220] have recently demonstrated that depletion of mitochondrial GSH in human umbilical vein endothelial cells (HUVECs) increased TNF-a-induced adhesion molecule (VCAM-1) expression but not ICAM-1 expression and mononuclear leukocyte adhesion in HUVECs, suggesting that mitochondrial GSH is involved in endothelial cell function [220].…”

Cannabinoid as a neuroprotective strategy in perinatal hypoxic-ischemic injury

“…However, studies in newborns have shown different levels of neuroprotection from hypothermia, either through inhibiting apoptotic cellular death and DNA fragmentation following hypoxia-ischemia [24,36] or through inducing a reduction in glutamate concentration at the synaptic space, a delay in the accumulation of intracellular calcium and a reduction in the production of nitric oxide [37,38] .…”

“…Despite the recovery of cerebral blood flow, many of these cells die in a process referred to as delayed cell death, whose cellular expression is programmed necrosis (necroptosis) and apoptosis [22][23][24][25][26][27][28] . It is these cells that appear to be more likely rescued, involving the search for therapeutic interventions that prevent the onset or interrupt the progression of destructive cascades.…”