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

Sally A Clayton,Giovanni Bottegoni,Triin Major,Kieran Woolcock,Andrew R Clark,Stefano Alivernini,Adeolu B Adewoye,John D O’Neil,Aziza Elmesmari,Christopher D Buckley,Daniel A Tennant,Lucy Macdonald,Andrew Filer,Simon W Jones,Qinqin Zhuang,Mariola Kurowska‐Stolarska ,Kalbinder K Daley ,Carl S Goodyear ,Erika Fernandez‐Vizarra ,Robert D S Pitceathly ,Daniel Patrick Griffin

doi:10.1126/sciadv.abl5182

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.

Highlights

Changes in activation state of immune cells are accompanied by, and dependent on, profound alterations of cellular metabolism [1, 2]
It has been demonstrated that metabolic pathways and mitochondrial activity contribute to autoimmune and chronic inflammatory pathologies such as rheumatoid arthritis (RA), underpinning the concept that these conditions might be effectively treated by targeting cellular metabolism [8–10]
In the orthologous mRNAs of coelacanth, a lobe-finned fish, and six randomly selected ray-finned fish, we found a maximum of two nucleotide differences within the miR-147b source sequence, none within the seed sequence that is the principal determinant of target specificity

Summary

Introduction

Changes in activation state of immune cells are accompanied by, and dependent on, profound alterations of cellular metabolism [1, 2]. An example of mitochondrial plasticity is the reprogramming of myeloid cells in response to activation or polarization cues. Stimulation of murine macrophages and dendritic cells with the pathogen-associated molecular pattern lipopolysaccharide (LPS) results in a Warburg-like metabolic state involving rapid up-regulation of glycolytic metabolism and lactate production. Mitochondria in these cells are described as being repurposed for the generation of reactive oxygen species (ROS), which have both signaling and direct bactericidal roles, as well as for the diversion of tricarboxylic acid (TCA) cycle metabolites into biosynthetic and immunoregulatory pathways [4–6]. It has been demonstrated that metabolic pathways and mitochondrial activity contribute to autoimmune and chronic inflammatory pathologies such as rheumatoid arthritis (RA), underpinning the concept that these conditions might be effectively treated by targeting cellular metabolism [8–10]

Methods

Results

Conclusion