Abstract
There is a growing body of evidence linking mitochondrial dysfunction, mediated either through inherited mitochondrial DNA (mtDNA) variation or mitochondrial proteomic deficit, to Parkinson's disease (PD). Yet, despite this, the role of somatic mtDNA point mutations and specifically point-mutational burden in PD is poorly understood. Here, we take advantage of recent technical and methodological advances to examine the role of age-related and acquired mtDNA mutation in the largest study of mtDNA in postmortem PD tissue to date. Our data show that PD patients suffer an increase in mtDNA mutational burden in, but no limited to, the substantia nigra pars compacta when compared to matched controls. This mutational burden appears increased in genes encoding cytochrome c oxidase, supportive of previous protein studies of mitochondrial dysfunction in PD. Accepting experimental limitations, our study confirms the important role of age-related mtDNA point mutation in the etiology of PD, moreover, by analyzing 2 distinct brain regions, we are able to show that PD patient brains are more vulnerable to mtDNA mutation overall.
Highlights
Mitochondria are critical subcellular organelles, charged with providing cellular energy through oxidative phosphorylation (OXPHOS) by the respiratory chain
Limiting to nonsynonomous heteroplasmic variation and further stratifying by mitochondrial DNA (mtDNA) locus revealed a significant overrepresentation of Parkinson’s disease (PD) cases harboring MTCOX1, MTCOX2, and MTCYTB variants in substantia nigra pars compacta (SNpc) and MTCYTB variants in frontal cortex (FC) tissue (Fig 1D and E)
Heteroplasmic variation in the DLOOP accounted for a large proportion of differential variation in both cases and controls, a phenomenon reported in similar studies (Supplementary Fig. 3) (Williams et al, 2013), and MTATP8, MTND4L, and MTDN4 appear well-conserved in both PD cases and controls, an indication of mutational intolerance in these particular subunits and again similar to published data
Summary
Mitochondria are critical subcellular organelles, charged with providing cellular energy (adenosine triphosphate [ATP]) through oxidative phosphorylation (OXPHOS) by the respiratory chain. Thirteen of the w90 OXPHOS proteins are encoded in by mitochondrial DNA (mtDNA); a highly mutable, maternally inherited, DNA molecule, which undergoes negligible intermolecular recombination. The breakdown of OXPHOS, a disruption of cellular energy supply and demand, often leads to disease and is mediated largely through a purported vicious cycle of reactive oxygen species dependent mutation formation (de Grey, 2005). Multiple lines of evidence implicate mitochondrial dysfunction in the pathogenesis of idiopathic PD, with genetic analysis focusing largely on the role of extant, inherited, mtDNA variants (Ghezzi et al, 2005; Hudson et al, 2013, 2014; Latsoudis et al, 2008). Reports have indicated that isolated mtDNA deletion formation is important (Bender et al, 2006; Kraytsberg et al, 2006), but the role of somatic single nucleotide variation has never been fully investigated in PD
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