Accessory subunit NDUFB4 participates in mitochondrial complex I supercomplex formation.

Autor: Parmar G; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ontario, Canada., Fong-McMaster C; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ontario, Canada., Pileggi CA; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ontario, Canada., Patten DA; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ontario, Canada., Cuillerier A; Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada., Myers S; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ontario, Canada., Wang Y; Department of Biology, McGill University, Montreal, Quebec, Canada., Hekimi S; Department of Biology, McGill University, Montreal, Quebec, Canada., Cuperlovic-Culf M; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ontario, Canada; National Research Council of Canada, Digital Technologies Research Centre, Ottawa, Ontario, Canada., Harper ME; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ontario, Canada. Electronic address: mharper@uottawa.ca.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2024 Feb; Vol. 300 (2), pp. 105626. Date of Electronic Publication: 2024 Jan 09.
DOI: 10.1016/j.jbc.2024.105626
Abstrakt: Mitochondrial electron transport chain complexes organize into supramolecular structures called respiratory supercomplexes (SCs). The role of respiratory SCs remains largely unconfirmed despite evidence supporting their necessity for mitochondrial respiratory function. The mechanisms underlying the formation of the I 1 III 2 IV 1 "respirasome" SC are also not fully understood, further limiting insights into these processes in physiology and diseases, including neurodegeneration and metabolic syndromes. NDUFB4 is a complex I accessory subunit that contains residues that interact with the subunit UQCRC1 from complex III, suggesting that NDUFB4 is integral for I 1 III 2 IV 1 respirasome integrity. Here, we introduced specific point mutations to Asn24 (N24) and Arg30 (R30) residues on NDUFB4 to decipher the role of I 1 III 2 -containing respiratory SCs in cellular metabolism while minimizing the functional consequences to complex I assembly. Our results demonstrate that NDUFB4 point mutations N24A and R30A impair I 1 III 2 IV 1 respirasome assembly and reduce mitochondrial respiratory flux. Steady-state metabolomics also revealed a global decrease in citric acid cycle metabolites, affecting NADH-generating substrates. Taken together, our findings highlight an integral role of NDUFB4 in respirasome assembly and demonstrate the functional significance of SCs in regulating mammalian cell bioenergetics.
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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