Parkinson Disorders Research Laboratory, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa, USA.
Laboratory of Environmental Epigenomes, Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
JCI Insight. 2021 Sep 8;6(17):e138088. doi: 10.1172/jci.insight.138088.
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.
线粒体功能障碍是帕金森病（PD）进展的主要病理生理因素；然而，它是否导致表观遗传失调仍不清楚。在这里，我们表明，化学和遗传驱动的线粒体功能障碍都具有共同的表观遗传失调机制。在这两种情况下，PD 多巴胺能神经元模型中的组蛋白 H3.3 赖氨酸 27 乙酰化（H3.3K27ac）增加，从而通过 H3K27ac 使该区域对活性增强子活性开放。这些脆弱的表观基因组位代表 PD 发病机制的潜在转录因子基序。我们进一步证实，线粒体功能障碍在 PD 的离体和体内（MitoPark）神经退行性模型中诱导 H3K27ac。值得注意的是，PD 大脑死后 H3K27ac 的显著增加突出了其与人类 PD 人群的临床相关性。我们的研究结果揭示了 PD 发病机制中令人兴奋的线粒体功能障碍-代谢-H3K27ac-转录组轴。总之，这些机制上的见解将线粒体功能障碍与多巴胺能变性中的表观遗传失调联系起来，并为 PD 提供了潜在的新的表观遗传干预策略。
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