TY - JOUR
T1 - Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48
AU - Clayton, Sally A.
AU - Daley, Kalbinder K.
AU - Macdonald, Lucy
AU - Fernandez-vizarra, Erika
AU - Bottegoni, Giovanni
AU - O’Neil, John D.
AU - Major, Triin
AU - Griffin, Daniel
AU - Zhuang, Qinqin
AU - Adewoye, Adeolu B.
AU - Woolcock, Kieran
AU - Jones, Simon W.
AU - Goodyear, Carl
AU - Elmesmari, Aziza
AU - Filer, Andrew
AU - Tennant, Daniel A.
AU - Alivernini, Stefano
AU - Buckley, Christopher D.
AU - Pitceathly, Robert D. S.
AU - Kurowska-stolarska, Mariola
AU - Clark, Andrew R.
PY - 2021/12/8
Y1 - 2021/12/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85120793064&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abl5182
DO - 10.1126/sciadv.abl5182
M3 - Article
SN - 2375-2548
VL - 7
JO - Science Advances
JF - Science Advances
IS - 50
M1 - eabl5182
ER -