Li Shuangshuang, Yang Guangdong
1 Cardiovascular and Metabolic Research Unit, Lakehead University , Thunder Bay, Ontario, Canada .
2 The School of Kinesiology, Lakehead University , Thunder Bay, Ontario, Canada .
Antioxid Redox Signal. 2015 Sep 1;23(7):630-42. doi: 10.1089/ars.2014.6186. Epub 2015 May 14.
Hydrogen sulfide (H2S) exerts a wide range of actions in the body, especially in the modulation of mitochondrial functions. The normal replication of mitochondrial DNA (mtDNA) is critical for cellular energy metabolism and mitochondrial biogenesis. The aim of this study was to investigate whether H2S affects mtDNA replication and the underlying mechanisms. We hypothesize that H2S maintains mtDNA copy number via inhibition of Dnmt3a transcription and TFAM promoter methylation.
Here, we demonstrated that deficiency of cystathionine gamma-lyase (CSE), a major H2S-producing enzyme, reduces mtDNA copy number and mitochondrial contents, and it inhibits the expressions of mitochondrial transcription factor A (TFAM) and mitochondrial marker genes in both smooth muscle cells and aorta tissues from mice. Supply of exogenous H2S stimulated mtDNA copy number and strengthened the expressions of TFAM and mitochondrial marker genes. TFAM knockdown diminished H2S-enhanced mtDNA copy number. In addition, CSE deficiency induced the expression of DNA methyltransferase 3a (Dnmt3a) and TFAM promoter DNA methylation, and H2S repressed Dnmt3a expression, resulting in TFAM promoter demethylation. We further found that H2S S-sulfhydrates transcription repressor interferon regulatory factor 1 (IRF-1) and enhances the binding of IRF-1 with Dnmt3a promoter after reduced Dnmt3a transcription. H2S had little effects on the expression of Dnmt1 and Dnmt3b as well as on ten-eleven translocation methylcytosine dioxygenase 1, 2, and 3.
A sufficient level of H2S is able to inhibit TFAM promoter methylation and maintain mtDNA copy number.
CSE/H2S system contributes to mtDNA replication and cellular bioenergetics and provides a novel therapeutic avenue for cardiovascular diseases.
硫化氢（H2S）在体内发挥多种作用，尤其是在调节线粒体功能方面。线粒体DNA（mtDNA）的正常复制对于细胞能量代谢和线粒体生物合成至关重要。本研究旨在探讨H2S是否影响mtDNA复制及其潜在机制。我们假设H2S通过抑制Dnmt3a转录和TFAM启动子甲基化来维持mtDNA拷贝数。
在此，我们证明了胱硫醚γ-裂解酶（CSE）（一种主要的H2S产生酶）的缺乏会降低mtDNA拷贝数和线粒体含量，并抑制小鼠平滑肌细胞和主动脉组织中线粒体转录因子A（TFAM）和线粒体标记基因的表达。外源性H2S的供应刺激了mtDNA拷贝数，并增强了TFAM和线粒体标记基因的表达。TFAM敲低减少了H2S增强的mtDNA拷贝数。此外，CSE缺乏诱导DNA甲基转移酶3a（Dnmt3a）的表达和TFAM启动子DNA甲基化，而H2S抑制Dnmt3a表达，导致TFAM启动子去甲基化。我们进一步发现，H2S使转录抑制因子干扰素调节因子1（IRF-1）发生S-硫巯基化，并在降低Dnmt3a转录后增强IRF-1与Dnmt3a启动子的结合。H2S对Dnmt1和Dnmt3b的表达以及对10-11易位甲基胞嘧啶双加氧酶1、2和3几乎没有影响。
足够水平的H2S能够抑制TFAM启动子甲基化并维持mtDNA拷贝数。
CSE/H2S系统有助于mtDNA复制和细胞生物能学，并为心血管疾病提供了一条新的治疗途径。
