Mitochondrial sulfide oxidation and persulfidation in mesenchymal stromal cell osteogenesis: Redox flux control as a unifying framework.

Hydrogen sulfide (H2S) regulates mitochondrial metabolism and thiol-dependent redox signaling. Central to its biological activity is mitochondrial sulfide oxidation, initiated by sulfide:quinone oxidoreductase (SQOR), which couples H2S catabolism to electron transport and persulfide generation. While sulfide signaling has been extensively characterized in stress adaptation and metabolic regulation, its integration with stem-cell fate decisions remains incompletely defined. Osteogenic differentiation of mesenchymal stromal cells (MSCs) requires coordinated mitochondrial remodeling, tightly constrained reactive oxygen species (ROS) signaling, and redox-sensitive transcriptional control, including RUNX2 stability. Emerging evidence indicates that H2S modulates these processes through persulfidation, respiratory modulation, and NRF2-dependent adaptation in a dose- and kinetics-dependent manner. We propose a redox-flux framework in which SQOR-dependent sulfide oxidation functions as a regulatory interface linking mitochondrial bioenergetics, reactive sulfur species signaling, and osteogenic lineage commitment. Translational relevance is discussed in relation to exposure paradigms, including sustained low-dose sulfide models, that may inform experimentally testable hypotheses on redox-adaptive osteogenesis.