Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, USA.
Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, USA.
Life Sci Alliance. 2019 Feb 8;2(1). doi: 10.26508/lsa.201800228. Print 2019 Feb.
The impact of mitochondrial dysfunction in epigenetics is emerging, but our understanding of this relationship and its effect on gene expression remains incomplete. We previously showed that acute mitochondrial DNA (mtDNA) loss leads to histone hypoacetylation. It remains to be defined if these changes are maintained when mitochondrial dysfunction is chronic and if they alter gene expression. To fill these gaps of knowledge, we here studied a progressive and a chronic model of mtDNA depletion using biochemical, pharmacological, genomics, and genetic assays. We show that histones are primarily hypoacetylated in both models. We link these effects to decreased histone acetyltransferase activity unrelated to changes in ATP citrate lyase, acetyl coenzyme A synthetase 2, or pyruvate dehydrogenase activities, which can be reversibly modulated by altering the mitochondrial pool of acetyl-coenzyme A. Also, we determined that the accompanying changes in histone acetylation regulate locus-specific gene expression and physiological outcomes, including the production of prostaglandins. These results may be relevant to the pathophysiology of mtDNA depletion syndromes and to understanding the effects of environmental agents that lead to physical or functional mtDNA loss.
线粒体功能障碍在表观遗传学中的影响正在显现，但我们对这种关系及其对基因表达的影响的理解还不完整。我们之前曾表明，急性线粒体 DNA（mtDNA）缺失会导致组蛋白低乙酰化。当线粒体功能障碍是慢性的时，这些变化是否仍然存在，以及它们是否会改变基因表达，仍有待确定。为了填补这些知识空白，我们在这里使用生化、药理学、基因组学和遗传学检测研究了渐进性和慢性 mtDNA 耗竭模型。我们表明，在这两种模型中，组蛋白主要呈低乙酰化。我们将这些影响与降低的组蛋白乙酰转移酶活性联系起来，该活性与 ATP 柠檬酸裂解酶、乙酰辅酶 A 合成酶 2 或丙酮酸脱氢酶活性的变化无关，这些活性可通过改变线粒体乙酰辅酶 A 池来可逆调节。此外，我们确定伴随的组蛋白乙酰化变化调节特定基因座的基因表达和生理结果，包括前列腺素的产生。这些结果可能与 mtDNA 耗竭综合征的病理生理学以及理解导致物理或功能 mtDNA 丧失的环境因素的影响有关。
