Mitochondria As Sources and Targets of Methane

This review summarizes the current knowledge on the role of mitochondria in the context of hypoxic cell biology, while providing evidence of how these mechanisms are modulated by methane (CH₄). Recent studies have unambiguously confirmed CH₄ bioactivity in various in vitro and in vivo experimental models and established the possibility that CH₄ can affect many aspects of mitochondrial physiology. To date, no specific binding of CH₄ to any enzymes or receptors have been reported, and it is probable that many of its effects are related to physico-chemical properties of the non-polar molecule. (i) Mitochondria themselves can be sources of endogenous CH₄ generation under oxido-reductive stress conditions; chemical inhibition of the mitochondrial electron transport chain with site-specific inhibitors leads to increased formation of CH₄ in eukaryote cells, in plants, and in animals. (ii) Conventionally believed as physiologically inert, studies cited in this review demonstrate that exogenous CH₄ modulates key events of inflammation. The anti-apoptotic effects of exogenously administered CH₄ are also recognized, and these properties also suggest that CH₄-mediated intracellular signaling is closely associated with mitochondria. (iii) Mitochondrial substrate oxidation is coupled with the reduction of molecular oxygen, thus providing energy for cellular metabolism. Interestingly, recent in vivo studies have shown improved basal respiration and modulated mitochondrial oxidative phosphorylation by exogenous CH₄. Overall, these data suggest that CH₄ liberation and effectiveness in eukaryotes are both linked to hypoxic events and redox regulation and support the notion that CH₄ has therapeutic roles in mammalian pathophysiologies.