Hydrogen sulfide and mitochondria: an intriguing paradox of survival and fate

Abstract

Hydrogen sulfide (H2S) has emerged as a critical gasotransmitter with profound implications for mitochondrial functions, challenging its historical classification as a mere toxic gas. Endogenously synthesized by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST), H2S plays a pivotal role in modulating mitochondrial respiration, ATP production, redox homeostasis, and overall bioenergetics by directly influencing cytochrome c oxidase and the electron transport chain. Beyond its metabolic roles, H2S is essential for mitochondrial biogenesis, underscoring its importance in cellular survival, stress adaption, and disease development. Dysregulation of H2S levels has been implicated in a wide spectrum of mitochondria-related disorders, including neurodegenerative disorders, cardiovascular diseases, and cancer, positioning H2S as a promising target for therapeutic intervention. This review gives an extensive analysis of the intricate relationship between H2S and mitochondrial physiology, underscoring its regulatory mechanisms, pathological outcomes, and therapeutic opportunities. By elucidating the molecular basis of H2S-mitochondria interactions, this review aims to advance the development of novel H2S-based interventions for mitochondrial dysfunctions and the associated diseases.