Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington’s disease

Abstract

Mitochondrial dysfunction is found in the brain and peripheral tissues of patients diagnosed with Huntington’s disease (HD), an irreversible neurodegenerative disease of which aging is a major risk factor. Mitochondrial function is encoded by not only nuclear DNA but also DNA within mitochondria (mtDNA). Expansion of mtDNA heteroplasmies (coexistence of mutated and wild-type mtDNA) can contribute to age-related decline of mitochondrial function but has not been systematically investigated in HD. Here, by using a sensitive mtDNA-targeted sequencing method, we studied mtDNA heteroplasmies in lymphoblasts and longitudinal blood samples of HD patients. We found a significant increase in the fraction of mtDNA heteroplasmies with predicted pathogenicity in lymphoblasts from 1,549 HD patients relative to lymphoblasts from 182 healthy individuals. The increased fraction of pathogenic mtDNA heteroplasmies in HD lymphoblasts also correlated with advancing HD stages and worsened disease severity measured by HD motor function, cognitive function, and functional capacity. Of note, elongated CAG repeats in HTT promoted age-dependent expansion of pathogenic mtDNA heteroplasmies in HD lymphoblasts. We then confirmed in longitudinal blood samples of 169 HD patients that expansion of pathogenic mtDNA heteroplasmies was correlated with decline in functional capacity and exacerbation of HD motor and cognitive functions during a median follow-up of 6 y. The results of our study indicate accelerated decline of mtDNA quality in HD, and highlight monitoring mtDNA heteroplasmies longitudinally as a way to investigate the progressive decline of mitochondrial function in aging and age-related diseases.

The Complicated Nature of Somatic mtDNA Mutations in Aging

“…For example, colonic epithelium has shown that normal aging in associated with an increase in clonal fields lacking OXPHOS activity that are the result of mtDNA mutations (Taylor et al, 2003;Greaves et al, 2014). Similar findings have been observed in stomach, prostate, and small intestines of normally aged individuals, as well as blood of Huntington's disease patients (Fellous et al, 2009;Greaves et al, 2010;Wang et al, 2021).…”

Cellular Allostatic Load is linked to Increased Energy Expenditure and Accelerated Biological Aging

“…We now turn our attention to potential maladaptive consequences of sustained allostatic load, namely evidence of mitochondrial and cellular allostatic overload. In vitro and in vivo studies have shown that one of the consequences of chronic metabolic stressors, OxPhos defects, and aging is mtDNA instability, manifested as the accumulation of mtDNA defects [50][51][52][53][54] . We also recently demonstrated that mtDNA instability can be induced by OxPhos defects in this cellular lifespan system 27 .…”

“…We next turned our attention to potential maladaptive consequences of sustained allostatic load, namely evidence of allostatic overload. In vitro and in vivo studies have shown that chronic metabolic stressors, primary energetic defects, and aging result in mtDNA instability, which manifest as the accumulation of mtDNA defects (53)(54)(55)(56)(57).…”

Players in Mitochondrial Dynamics and Female Reproduction

“…Disruption of mitochondrial activity may be associated with PD, especially under the dysfunction of PINK1 and Parkin. PINK1 and Parkin are localized in the mitochondria ( Wang et al, 2021 ). PINK1 protects against mitochondrial dysfunction under stress by phosphorylating mitochondrial proteins.…”

“…HTT mutants could accumulate in the body and trigger DRP1 dysfunction, leading to mitochondrial transport abnormalities and ultimately leading to neuronal apoptosis ( Song et al, 2011 ; Shirendeb et al, 2012 ). Of note, long CAG repeats in HTT could promote the age-dependent expansion of pathogenic mtDNA heteroplasmy in HD lymphoblasts ( Wang et al, 2021 ). Thus, they concluded that mtDNA quality is declining along with the HD’s process, indicating a role of HTT in mtDNA quality control.…”