Figure 1.

Homocysteine, by activating matrix metalloproteinase-9 (MMP-9) facilitates the damage of mitochondria, and by inhibiting the transcriptional activity of nuclear factor erythroid 2-related factor (Nrf2), damages the defense system. By supplying S-adenosyl methionine (SAM), it helps in the DNA methylation process and the hypermethylation of mitochondrial DNA (mtDNA) and that of POLG and MLH1 and impairs the electron transport chain by interfering with the transcription, biogenesis, and repair of damaged mtDNA. The vicious cycle of free radicals continues to self-propagate. Homocysteine can also increase inflammation and endoplasmic reticulum (ER) stress and other pathways implicated in mitochondrial damage.