Role of oxidative DNA damage in mitochondrial dysfunction and Huntington's disease pathogenesis

Abstract

Huntington's disease (HD) is a neurodegenerative disorder with an autosomal dominant expression pattern and typically a late-onset appearance. HD is a movement disorder with a heterogeneous phenotype characterized by involuntary dance-like gait, bioenergetic deficits, motor impairment, and cognitive and psychiatric deficits. Compelling evidence suggests that increased oxidative stress and mitochondrial dysfunction may underlie HD pathogenesis. However, the exact mechanisms underlying mutant huntingtin-induced neurological toxicity remain unclear. The objective of this paper is to review recent literature regarding the role of oxidative DNA damage in mitochondrial dysfunction and HD pathogenesis.

Keywords: 3-NPA; 3-nitropropionic acid; 7,8-dihydro-8-oxoguanine-DNA glycosylase; 8-OHdG; 8-hydroxydeoxyguanosine; AP; ARE; ATM; ATR; BER; DNA repair; FEN1; HD; Huntington’s disease; MMR; Mitochondrial DNA; Mitochondrial bioenergetics; Mitochondrial dysfunction; NF-E2-related factor 2; Nrf2; OGG1; Oxidative stress; PGC-1α; POL β; PPARγ; ROS; Rad3-related kinase; Sirt; antioxidant response element; apurinic/apyrimidinic; ataxia telangiectasia mutated kinase; base excision repair; flap endonuclease 1; mismatch repair; peroxisome proliferator-activated receptor-γ; peroxisome proliferator-activated receptor-γ coactivator-1 α; polymerase beta; reactive oxygen species; sirtuins.

Figure 1

Vicious cycle of mitochondrial oxidative damage in HD. Under the context of mutant huntingtin (htt) expression, mitochondria lead to overproduction of mitochondrial ROS that introduce oxidative damage to the mitochondria. Damaged mtDNA leads to dysfunctional mitochondrial bioenergetics that generate additional ROS and exacerbates oxidative damage to mtDNA, ultimately leading to HD pathophysiology. Thus, mtDNA damage in the form of oxidative lesions and mtDNA depletion may ultimately interfere with mitochondrial function resulting in diminished ATP synthesis, increased ROS production and exacerbation of oxidative damage to mtDNA.

Figure 2

Model of oxidative DNA damage and mitochondrial dysfunction in HD. A possible mechanism underlying the toxic effects of mutant huntingtin (htt) is the accumulation of mtDNA lesions and the occurrence of mtDNA depletion as a result of increases in mitochondrial ROS generation. Concurrently, mutant huntingtin affects mtDNA repair by preventing the accumulation of APE1 in the mitochondria, thus contributing to further mitochondrial damage. Consistent with this hypothesis, mtDNA damage leads to exacerbated mitochondrial dysfunction and HD-like neurodegeneration. Oxidative damage to nDNA also contributes to mitochondrial dysfunction and leads to the activation of DNA repair processes that may lead to CAG repeat expansion.