Abstract
Mitochondrial dysfunction is a major pathophysiological contributor to the progression of Parkinson’s disease (PD); however, whether it contributes to epigenetic dysregulation remains unknown. Here, we show that both chemically and genetically driven mitochondrial dysfunctions share a common mechanism of epigenetic dysregulation. Under both scenarios, lysine 27 acetylation of likely variant H3.3 (H3.3K27ac) increased in dopaminergic neuronal models of PD, thereby opening that region to active enhancer activity via H3K27ac. These vulnerable epigenomic loci represent potential transcription factor motifs for PD pathogenesis. We further confirmed that mitochondrial dysfunction induces H3K27ac in ex vivo and in vivo (MitoPark) neurodegenerative models of PD. Notably, the significantly increased H3K27ac in postmortem PD brains highlights the clinical relevance to the human PD population. Our results reveal an exciting mitochondrial dysfunction-metabolism-H3K27ac-transcriptome axis for PD pathogenesis. Collectively, the mechanistic insights link mitochondrial dysfunction to epigenetic dysregulation in dopaminergic degeneration and offer potential new epigenetic intervention strategies for PD.
Highlights
Since the first reports of SNCA mutation in the pathogenesis of Parkinson’s disease (PD) [1], investigations on genetic causes in PD have flourished and gained mainstream attention in the scientific community
Consistent with our previous data [9, 10] as well as published studies [21, 22], these results suggest that PD-related mitochondrial impairment induces H3 hyperacetylation
These results indicate that large numbers of enhancers defined by the H3K27ac mark were sensitive to mitochondrial impairment, which has implications for enhancer-specific gene regulation related to PD pathogenesis
Summary
Since the first reports of SNCA mutation in the pathogenesis of Parkinson’s disease (PD) [1], investigations on genetic causes in PD have flourished and gained mainstream attention in the scientific community. Genetic mutations at 15 loci explain only about 10%–15% of PD cases [2, 3]. Mutations of several key PD genes, including PARK2 (Parkin), PARK6 (PINK1), SNCA, and LRRK2, modify key mitochondrial functions [4, 5].environmental exposure and its interactions with genetic factors are expected to explain most PD cases. Many environmental neurotoxicants are known to impair mitochondrial functions. The pesticide rotenone inhibits mitochondrial functionality by impairing oxidative phosphorylation and protein synthesis, leading to energy depletion [6, 7]. Mitochondrial dysfunction is key for both genetically and environmentally linked PD; the underlying mechanism remains unclear
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