Mitochondrial DNA damage Is associated with reduced mitochondrial bioenergetics in Huntington's disease

Abstract

Oxidative stress and mitochondrial dysfunction have been implicated in the pathology of HD, however the precise mechanisms by which mutant huntingtin modulates levels of oxidative damage in turn resulting in mitochondrial dysfunction are not known. We hypothesize that mutant huntingtin increases oxidative mtDNA damage leading to mitochondrial dysfunction. We measured nuclear and mitochondrial DNA lesions and mitochondrial bioenergetics in the STHdhQ7 and STHdhQ111 in vitro striatal model of HD. Striatal cells expressing mutant huntingtin show higher basal levels of mitochondrial-generated ROS and mtDNA lesions and a lower spare respiratory capacity. Silencing of APE1, the major mammalian apurinic/apyrimidinic (AP) endonuclease that participates in the base excision repair (BER) pathway, caused further reductions of spare respiratory capacity in the mutant huntingtin-expressing cells. Localization experiments show that APE1 increases in the mitochondria of wild type Q7 cells but not in the mutant huntingtin Q111 cells after treatment with hydrogen peroxide. Moreover, these results are recapitulated in human HD striata and HD skin fibroblasts that show significant mtDNA damage (increased lesion frequency and mtDNA depletion) and significant decreases in spare respiratory capacity, respectively. These data suggest that mtDNA is a major target of mutant huntingtin-associated oxidative stress and may contribute to subsequent mitochondrial dysfunction and that APE1 (and, by extension, BER) is an important target in the maintenance of mitochondrial function in HD.

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

“…The mitochondrial dysfunction pathway has 37 DEGs, while there are 42 DEGs in the Huntington's disease signaling pathway. Mitochondrial dysfunction is believed to play a role in Huntington's disease pathology, and prior studies have demonstrated that APE1 is important for the maintenance of mitochondrial function (Li et al ., 2012; Siddiqui et al ., 2012). APE1 is also known to participate in mitochondrial DNA repair functions (Ballista‐Hernandez et al ., 2017; Stuart et al ., 2004; Vascotto et al ., 2009).…”

“…One previously linked pathway of particular interest is the mitochondrial dysfunction pathway. APE1 redox and repair activity has previously been shown to be responsible for maintaining and repairing mitochondrial DNA (Ballista‐Hernandez et al ., 2017; Li et al ., 2012; Siddiqui et al ., 2012; Stuart et al ., 2004; Vascotto et al ., 2009). The results of our studies presented here identify, for the first time, the genes responsible for these functions.…”

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

“…Indeed, the striatum is highly susceptible to dysfunction of mitochondrial oxidative phosphorylation [92]. ROS formation in HD can further damage mitochondria by dissipating the mitochondrial membrane potential, dysregulating ATP production and leading to oxidation of mtDNA [8,23,93], which is highly vulnerable to oxidative damage due to its proximity to the respiratory chain, limited repair mechanisms, few non-coding sequences and lack of histones [94]. We have previously shown that O 2 x-formation also rises in HD human cybrids following exposure to 3-nitropropionic acid or staurosporine [43].…”

Exercise training normalizes mitochondrial respiratory capacity within the striatum of the R6/1 model of Huntington’s disease

“…Analyses of mitochondrial content and function in HD have demonstrated decreases in the protein content of electron transport chain complexes II & III, along with decreases in the activity of complexes II/III & IV (Mann et al, 1990;Gu et al, 1996;Browne et al, 1997). Decreased mitochondrial DNA (mtDNA) abundance has also been observed (Horton et al, 1995) along with increases in mtDNA lesion frequency (Siddiqui et al, 2012), indicating that the mitochondrial genome is damaged by mHtt. Further, support for a causative role of mitochondrial dysfunction in HD pathology comes from observations where exposure of healthy animals to the mitochondrial complex II inhibitor 3-nitropropionic acid (Brouillet et al, 1995) can also result in striatal degeneration and produce symptoms similar to those observed in animal models of HD.…”