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ORIGINAL RESEARCH ARTICLE

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

Grace Russell1,2*
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1 Department of Research and Development, Water Fuel Engineering, Wakefield, Yorkshire, United Kingdom
2 School of Applied Science, College of Health and Social Sciences, University of the West of England (UWE), Bristol, United Kingdom
MI, 4544 https://doi.org/10.36922/mi.4544
Submitted: 15 August 2024 | Accepted: 10 October 2024 | Published: 18 November 2024
(This article belongs to the Special Issue Hydrogen and the Human Microbiome)
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

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.

Keywords
Complex I
Evolution
Hydrogen
Hydrogenases
Redox activity
NDUFS7
Oxidative stress
Funding
This research was co-funded by Water Fuel Engineering and the University of the West of England. Funding identification number 7096050. Project code: RDAS0184.
Conflict of interest
This work was part-funded by Water Fuel Engineering, a manufacturer of oxy-hydrogen inhalation devices. Grace Russell is the Guest Editor of this special issue but was not involved in the editorial or peer-review processes for this paper, either directly or indirectly.
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