title: Hydrogen Sulfide Maintains Mitochondrial DNA Replication via Demethylation of TFAM.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  METHODS
  A sufficient level of H2S is able to inhibit TFAM promoter methylation and maintain mtDNA copy number.
  
  
  CONCLUSIONS
  CSE/H2S system contributes to mtDNA replication and cellular bioenergetics and provides a novel therapeutic avenue for cardiovascular diseases.
authors.affiliation: 1 Cardiovascular and Metabolic Research Unit, Lakehead University , Thunder Bay, Ontario, Canada .|2 The School of Kinesiology, Lakehead University , Thunder Bay, Ontario, Canada .
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Li
authors.affiliation: 1 Cardiovascular and Metabolic Research Unit, Lakehead University , Thunder Bay, Ontario, Canada .|2 The School of Kinesiology, Lakehead University , Thunder Bay, Ontario, Canada .
authors.forename: Guangdong
authors.initials: G
authors.lastname: Yang
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000172:deficiency; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D018628:Gene Dosage; D055786:Gene Knockout Techniques; D006609:High Mobility Group Proteins / Q000235:genetics*; D006862:Hydrogen Sulfide / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; C000715535:Dnmt3a protein, mouse; D006609:High Mobility Group Proteins; C081930:Tfam protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide