Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48

Clayton, S. A. et al. (2021) Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48. Science Advances, 7(50), eabl5182. (doi: 10.1126/sciadv.abl5182) (PMID:34878835)

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Abstract

Dysregulated mitochondrial function is a hallmark of immune-mediated inflammatory diseases. Cytochrome c oxidase (CcO), which mediates the rate-limiting step in mitochondrial respiration, is remodeled during development and in response to changes of oxygen availability, but there has been little study of CcO remodeling during inflammation. Here, we describe an elegant molecular switch mediated by the bifunctional transcript C15orf48, which orchestrates the substitution of the CcO subunit NDUFA4 by its paralog C15ORF48 in primary macrophages. Expression of C15orf48 is a conserved response to inflammatory signals and occurs in many immune-related pathologies. In rheumatoid arthritis, C15orf48 mRNA is elevated in peripheral monocytes and proinflammatory synovial tissue macrophages, and its expression positively correlates with disease severity and declines in remission. C15orf48 is also expressed by pathogenic macrophages in severe coronavirus disease 2019 (COVID-19). Study of a rare metabolic disease syndrome provides evidence that loss of the NDUFA4 subunit supports proinflammatory macrophage functions.

Item Type:Articles
Additional Information:This work was supported by Programme Grant 21802 and Research into Inflammatory Arthritis Centre Versus Arthritis (22072), both from Versus Arthritis, UK
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacDonald, Miss Lucy and Woolcock, Kieran and Fernandez-Vizarra, Dr Erika and Alivernini, Mr Stefano and Elmesmari, Dr Aziza and Filer, Dr Andrew and Buckley, Professor Christopher and Goodyear, Professor Carl and Kurowska-Stolarska, Dr Mariola
Authors: Clayton, S. A., Daley, K. K., MacDonald, L., Fernandez-Vizarra, E., Bottegoni, G., O’Neil, J. D., Major, T., Griffin, D., Zhuang, Q., Adewoye, A. B., Woolcock, K., Jones, S. W., Goodyear, C., Elmesmari, A., Filer, A., Tennant, D. A., Alivernini, S., Buckley, C. D., Pitceathly, R. D. S., Kurowska-Stolarska, M., and Clark, A. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Science Advances
Publisher:American Association for the Advancement of Science
ISSN:2375-2548
ISSN (Online):2375-2548
Published Online:08 December 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Science Advances 7(50): eabl5182
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
303229RACE RenewalIain McInnesVersus Arthritis (ARTRESUK)NW/22072III - Immunology