Hydrogen Sulfide Maintains Mitochondrial DNA Replication via Demethylation of TFAM

Abstract

Aims: Hydrogen sulfide (H 2 S) 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 H 2 S affects mtDNA replication and the underlying mechanisms. We hypothesize that H 2 S 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 H 2 S-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 H 2 S stimulated mtDNA copy number and strengthened the expressions of TFAM and mitochondrial marker genes. TFAM knockdown diminished H 2 S-enhanced mtDNA copy number. In addition, CSE deficiency induced the expression of DNA methyltransferase 3a (Dnmt3a) and TFAM promoter DNA methylation, and H 2 S repressed Dnmt3a expression, resulting in TFAM promoter demethylation. We further found that H 2 S S-sulfhydrates transcription repressor interferon regulatory factor 1 (IRF-1) and enhances the binding of IRF-1 with Dnmt3a promoter after reduced Dnmt3a transcription. H 2 S had little effects on the expression of Dnmt1 and Dnmt3b as well as on ten-eleven translocation methylcytosine dioxygenase 1, 2, and 3. Innovation: A sufficient level of H 2 S is able to inhibit TFAM promoter methylation and maintain mtDNA copy number. Conclusion: CSE/H 2 S system contributes to mtDNA replication and cellular bioenergetics and provides a novel therapeutic avenue for cardiovascular diseases. Antioxid. Redox Signal. 23, 630-642.

Inhibition of hydrogen sulfide biosynthesis sensitizes lung adenocarcinoma to chemotherapeutic drugs by inhibiting mitochondrial DNA repair and suppressing cellular bioenergetics

“…Using a recently developed mitochondrial-specific H 2 S donor, AP3930, we have shown previously that mitochondria-specific H 2 S delivery significantly reduces amount of mtDNA damaged induced by oxidative stress in cultured endothelial cells, suggesting a stimulatory role of H 2 S in process of the mtDNA repair16. Another report demonstrated that cells deficient in H 2 S production (due to CSE deficiency), have reduced number of mtDNA copies42. Thus - although a correlation between H 2 S and mtDNA damage/repair has been implicated - the molecular mechanisms of how H 2 S regulates the integrity of the mtDNA, and how these processes are important for the tumorigenic potential of cancer cells is currently unknown.…”

Mitochondrial pathways to cardiac recovery: TFAM

“…More specifically, exogenous H2S improved mtDNA copy number and increased TFAM expression. H2S functions to diminish DNA methlytransferase 3a (DNMT3a) resulting in TFAM demethylation, it also sulfhydrates interferon regulatory factor 1 (IRF-1) which increases the binding of IRF-1 to the DNMT3a promoter [45]. These treatment methods target TFAM’s regulation over mtDNA copy number [1].…”

The role of hydrogen sulfide in aging and age-related pathologies

“…Supply of H 2 S-releasing compounds rescued these cells from the harmful effects of high levels of circulatory homocysteine [123, 124]. Hydrogen sulfide alters the epigenetics of the mitochondrial genome, contributing to the replication of mitochondrial DNA, cellular energy metabolism and mitochondrial bioenergetics [125]. Exogenous H 2 S repressed the expression of DNA methyltransferase in cultured smooth muscle cells and aortic tissues from mice, resulting in the demethylation of certain regions of the mitochondrial genome, whereas CSE deficiencies showed opposite effects [125].…”