Investigation of hydrogenase enzymes and the presence of orthologs in the human proteome

Hydrogenase enzymes catalyze the reversible oxidation/reduction of hydrogen (H2) and play a crucial role in microbial energy metabolism, with significant implications for human immunity. H2, produced by gut microbes during fermentation or administered exogenously, is vital in modulating oxidative stress and inflammation. In the gastrointestinal tract, microbial H2 production can reach up to 13 L/day, with approximately 71% of commensal bacteria capable of metabolizing H2. By interacting with complex I, particularly the NDUFS7 subunit, H₂ may reduce mitochondrial electron leakage and limit the generation of reactive oxygen species (ROS). Excessive ROS can trigger pro-inflammatory signaling and impair immune responses. This study investigated the presence of hydrogenase orthologs in the human proteome, particularly within mitochondrial complex I, and their potential role in immune function. This novel research highlights a possible evolutionary link between microbial hydrogenases and human immunity, suggesting that microbial-derived H2 may support immune homeostasis by mitigating oxidative stress and inflammation. Although human homologs of nickel/iron hydrogenases, such as NDUFS2 and NDUFS7, likely lack classical hydrogenase activity, sequence similarities between NDUFS7 and hydrogenase subunits in Asgard archaea and δ-proteobacteria indicate the conservation of potential redox-active sites. Redox activity, occurring at the N2 iron-sulfur cluster in NDUFS7, may influence mitochondrial oxidative stress responses, which are integral to immune regulation. These findings open new avenues for exploring the therapeutic potential of H₂ in immune regulation.