(A) Interferon regulatory factor 1 (IRF-1) is a transcriptional repressor of the DNA methyltransferase 3a (Dnmt-3a). IRF-1 is regulated by sulfhydration. When H2S levels and consequently sulfhydration levels are low, IRF-1 is unable to bind its site on the Dnmt-3a promoter, leading to increased expression of Dnmt-3a, which methylates its target promoters, including the mitochondrial transcription factor A (TFAM), leading to reduced mitochondrial biogenesis. (B) When H2S production is increased, it sulfhydrates IRF-1 and enhances its interaction with the Dnmt-3a promoter to repress its expression. Consequently, methylation of the TFAM promoter is decreased, leading to a higher expression of TFAM and increased mitochondrial biogenesis.