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

Dysregulated mitochondrial function is a hallmark of immune-mediated inflammatory diseases. Cytochrome oxidase (CO), 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 CO remodeling during inflammation. Here, we describe an elegant molecular switch mediated by the bifunctional transcript , which orchestrates the substitution of the CO subunit NDUFA4 by its paralog C15ORF48 in primary macrophages. Expression of is a conserved response to inflammatory signals and occurs in many immune-related pathologies. In rheumatoid arthritis, mRNA is elevated in peripheral monocytes and proinflammatory synovial tissue macrophages, and its expression positively correlates with disease severity and declines in remission. 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.