Clayton 2024 Abstract IOC163

From Bioblast
Clayton SA, Daley KK, O’Neil JD, MacDonald L, Mahida R, Pitceathly RDS, Kurowska-Stolarska M, Fernandez-Vizarra E, Dimeloe S, Clark AR (2024) Investigating the role of the NDUFA4 (COXFA4) family of electron transport chain proteins in inflammation. Mitochondr Physiol Network 28.11.

Link: IOC163

Clayton Sally A, Daley Kalbinder K, O’Neil John D, MacDonald Lucy, Mahida Rahul, Pitceathly Robert DS, Kurowska-Stolarska Mariola, Fernandez-Vizarra Erika, Dimeloe Sarah, Clark Andrew R (2024)

Event: IOC163

Mitochondrial dynamics underlie the function of immune cells in health and disease. Regulation of electron transport chain (ETC) subunit composition has been demonstrated during tissue development and under hypoxia (1), however the relevance of this regulatory mechanism to the immune system is poorly understood. We investigated the dynamics and function of the NDUFA4 (aka COXFA4) family of cytochrome c oxidase subunits during inflammation (2).

Macrophages were differentiated in vitro from human peripheral blood or from mouse bone marrow. Primary alveolar macrophages were isolated from patients undergoing lung resection surgery. Gene expression was determined by RT-qPCR and from public datasets. Protein expression was determined by Western blotting and Luminex assay, and blue-native electrophoresis was used to assess ETC organisation.

We identified that the little-studied gene C15orf48 encodes a novel isoform of the NDUFA4 subunit family. C15orf48 expression is induced by macrophage toll-like receptor activation, leading to C15ORF48 protein replacing the NDUFA4 subunit within ETC complex IV. C15orf48 is strongly upregulated in LPS-treated primary human alveolar macrophages and in inflammation-associated diseases including sepsis and COVID-19. Macrophages from individuals lacking NDUFA4 expression show elevated cytokine and chemokine production, suggesting that these proteins help to regulate macrophage inflammatory function.

We have generated a C15orf48-KO mouse model that will be used to further investigate the role of this mitochondrial axis, with the aim of identifying metabolic and phenotypic impacts of C15orf48 loss on the immune system and inflammatory diseases.

We demonstrate that immune activation is a previously unrecognised cue for mitochondrial ETC subunit exchange, relevant to multiple inflammatory pathologies. Understanding this conserved regulatory event will shine new light on how mitochondrial processes instruct the immune response.


β€’ Bioblast editor: Plangger M β€’ O2k-Network Lab: IT Padova Viscomi C


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Affiliations

Sally A Clayton (1), Kalbinder K Daley (1), John D O’Neil (1), Lucy MacDonald (2), Rahul Mahida (1), Robert D S Pitceathly (3), Mariola Kurowska-Stolarska (2), Erika FernΓ‘ndez-Vizarra (4), Sarah Dimeloe (1), Andrew R Clark (1)
  1. School of Infection, Inflammation, and Immunology, University of Birmingham, Birmingham, UK;
  2. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK;
  3. Queen Square Institute of Neurology, UCL, London, UK;
  4. Department of Biomedical Sciences, University of Padova, Padova, Italy.


References

  1. Sinkler et al. Oxid Med Cell Longev. (2017) doi: 10.1155/2017/1534056
  2. Clayton et al. Science Advances (2021) doi: 10.1126/sciadv.abl5182
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