Lack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stress

Abstract

Genomic instability drives tumorigenesis and DNA repair defects are associated with elevated cancer. Metabolic alterations are also observed during tumorigenesis, although a causal relationship between these has not been clearly established. Xeroderma pigmentosum (XP) is a DNA repair disease characterized by early cancer. Cells with reduced expression of the XPC protein display a metabolic shift from OXPHOS to glycolysis, which was linked to accumulation of nuclear DNA damage and oxidants generation via NOX-1. Using XP-C cells, we show that mitochondrial respiratory complex I (CI) is impaired in the absence of XPC, while complex II (CII) is upregulated in XP-C cells. The CI/CII metabolic shift was dependent on XPC, as XPC complementation reverted the phenotype. We demonstrate that mitochondria are the primary source of H2O2 and glutathione peroxidase activity is compromised. Moreover, mtDNA is irreversibly damaged and accumulates deletions. XP-C cells were more sensitive to the mitochondrial inhibitor antimycin A, an effect also prevented in XPC-corrected cells. Our results show that XPC deficiency leads to alterations in mitochondrial redox balance with a CI/CII shift as a possible adaptation to lower CI activity, but at the cost of sensitizing XP-C cells to mitochondrial oxidative stress.

Evidence of Oxidative Stress and Secondary Mitochondrial Dysfunction in Metabolic and Non-Metabolic Disorders

“…Evidence of mitochondrial dysfunction in XP has been indicated by mitochondrial DNA (mtDNA) deletions [ 150 , 151 ], ETC enzyme dysfunction [ 147 , 152 ] and morphological abnormalities [ 153 , 154 ]. Interestingly, studies have suggested that mitochondria are the major source of ROS generation in human XP-C cells and that mtDNA is the primary target for damage accumulation [ 152 ]. Since mtDNA lacks an NER, with repair being elicited through other mechanisms [ 155 ], this does suggest that mitochondrial abnormalities reported in XP are a secondary consequence of abnormalities in the nuclear DNA repair system.…”

“…Decreased activities of the antioxidant enzymes, catalase [ 156 ], SOD (superoxide dismutase) [ 143 ] and GSH-PX [ 152 ] have been reported in patient tissue and cell models of XP. In addition, decreased plasma CoQ 10 levels were reported in patients with XP, with improvements in their daily activity being documented in a subset of these patients following CoQ 10 supplementation [ 157 ].…”

Role of mitochondrial dysfunction in the pathophysiology of DNA repair disorders

“…In locus correction of XPC defect with WT XPC reverted all bioenergetics parameters, but not mtDNA damage and deletion. Finally, the XPC‐associated imbalanced CI/CII activity led to increased sensitivity of XP‐C cells to mitochondrial oxidative stress, which was completely corrected by WT XPC expression (Mori et al, ).…”

PPRC1, but not PGC-1α, levels directly correlate with expression of mitochondrial proteins in human dermal fibroblasts

“…We have recently reported that XP-C cells display a shift between respiratory complexes I and II utilization, accompanied with increased mitochondrial H 2 O 2 production and decreased GPx activity (Mori et al, 2017). Moreover, this shift between complex I and II resulted in an increased cellular sensitivity to mitochondrially induced redox unbalance that was fully reverted in an isogenic corrected XP-C cell line.…”