Accessory subunit NDUFB4 participates in mitochondrial complex I supercomplex formation

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DOI

Resolve DOI: https://doi.org/10.1016/j.jbc.2024.105626

Author

Search for: Parmar, Gaganvir; Search for: Fong-McMaster, Claire; Search for: Pileggi, Chantal A.; Search for: Patten, David A.; Search for: Cuillerier, Alexanne; Search for: Myers, Stephanie; Search for: Wang, Ying; Search for: Hekimi, Siegfried; Search for: Cuperlovic-Culf, Miroslava¹; Search for: Harper, Mary-Ellen ORCID identifier: https://orcid.org/0000-0003-3864-5886

Affiliation

National Research Council of Canada. Digital Technologies

Format

Text, Article

Subject

mitochondria; electron transport chain; supercomplexes; NDUFB4; oxidative phosphorylation; respirasome; steady-state metabolomics

Abstract

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 I₁III₂IV₁ “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 I₁III₂IV₁ respirasome integrity. Here, we introduced specific point mutations to Asn24 (N24) and Arg30 (R30) residues on NDUFB4 to decipher the role of I₁III₂-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 I₁III₂IV₁ 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.

Publication date

2024-01-09

Publisher

Elsevier
American Society for Biochemistry and Molecular Biology

Licence

Creative Commons Attribution 4.0 International (CC BY 4.0)
https://creativecommons.org/licenses/by/4.0/

Language

English

Peer reviewed

Yes

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Record identifier

2660be1b-52fa-4585-bcbc-fa0950588119

Record created

2024-02-13

Record modified

2024-02-13

Date modified:: 2024-07-17