Mitochondrial matrix P53 sensitizes cells to oxidative stress

Abstract

A mitochondrial matrix-specific p53 construct (termed p53–290) in HepG2 cells was utilized to determine the impact of p53 in the mitochondrial matrix following oxidative stress. H2O2 exposure reduced cellular proliferation similarly in both p53–290 and vector cells, and p53–290 cells demonstrating decreased cell viability at 1 mM H2O2 (~85% viable). Mitochondrial DNA (mtDNA) abundance was decreased in a dose-dependent manner in p53–290 cells while no change was observed in vector cells. Oximetric analysis revealed reduced maximal respiration and reserve capacity in p53–290 cells. Our results demonstrate that mitochondrial matrix p53 sensitizes cells to oxidative stress by reducing mtDNA abundance and mitochondrial function.

Asbestos-Induced Pulmonary Fibrosis Is Augmented in 8-Oxoguanine DNA Glycosylase Knockout Mice

“…These findings are in accord with recent work from our group showing that overexpression of mt-hOGG1 WT, mt-hOGG1 Mut, and ACO-2 in AECs attenuate the P53 DNA damage response (16). Our data are also in agreement with studies showing that P53 activation is required for oxidant-induced apoptosis in hOGG1-deficient human fibroblasts (56) and that P53 can sensitize HepG2 cells to oxidative stress by reducing mtDNA (57). Accumulating studies suggest a key association between P53, OGG1, and ACO-2, including (1) P53 regulates OGG1 gene transcription in colon and renal epithelial cells (56), (2) P53-deficient cells have reduced OGG1 protein expression and activity (56), and (3) P53 can reduce ACO-2 gene expression and activity (58,59).…”

Mitochondria-targeted Ogg1 and Aconitase-2 Prevent Oxidant-induced Mitochondrial DNA Damage in Alveolar Epithelial Cells

“…Our results herein showing p53 mitochondrial expression in the setting of mtDNA damage concur with our earlier study showing that p53 mediates asbestos-induced AEC p53 mitochondrial translocation and intrinsic apoptosis (19). In accord with our findings, p53 activation is required for H 2 O 2 -induced apoptosis in hOgg1-deficient human fibroblast cells (28), and mitochondrial matrix p53 sensitizes HepG2 cells to oxidative stress by reducing mtDNA (43). Several lines of evidence demonstrate a potentially key association between p53, Ogg1, and Aco-2 including; 1) p53 regulates the transcription of the OGG1 gene in colon and renal epithelial cells (28), 2) p53-deficient cells have reduced Ogg1 protein expression and activity (28), and 3) p53 can reduce Aco-2 gene expression as well as Aco-2 activity (44,45).…”

The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis

“…Interestingly, mitochondria-targeted OGG1 diminishes ventilator-induced lung injury in mice by reducing the levels of mtDNA damage in the lungs [ 107 ]. Accumulating evidences also support an important association between p53, OGG1, and ACO-2, including (1) p53 regulates OGG1 gene transcription in colon and renal epithelial cells [ 93 ]; (2) p53 deficient cells have reduced OGG1 protein expression and activity [ 93 ]; (3) p53 can reduce Aco-2 gene expression [ 108 ]; (4) p53 activation is required for oxidant-induced apoptosis in OGG1 -deficient human fibroblasts [ 93 ]; and (5) p53 sensitizes HepG2 cells to oxidative stress by reducing mtDNA [ 109 ]. Collectively, these data support a key role for p53 in modulating AEC mtDNA damage in the pro-fibrotic lung response following asbestos exposure that also has important implications for our understanding of the malignant potential of asbestos fibers.…”