Inflammation-induced reprogramming of the mitochondrial cytochrome c oxidase complex: mechanisms and consequences.

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The C15orf48 gene is consistently induced by pro-inflammatory stimuli in many cell types, but has been little studied, and its systematic name provides little clue to its function. We show that C15orf48 mRNA has two important products: a short polypeptide of 83 amino acids; and the micro-RNA miR-147b, which is generated from the 3’ untranslated region. miR-147b specifically decreases expression of NDUFA4, a component of the mitochondrial cytochrome c oxidase (CcO) complex. The protein product of C15orf48 is structurally related to NDUFA4, and replaces NDUFA4 in the CcO complex. The expression of C15orf48 mRNA correlates with disease severity in RA; is elevated in pro-inflammatory macrophage subsets in RA; and is reduced in RA patients in remission of disease. Expression of C15orf48 mRNA is also elevated in several inflammatory pathologies including psoriasis, stroke, hepatitis, sepsis and severe COVID-19. I will discuss how macrophage function is influenced by the economical molecular switch between NDUFA4 and C15ORF48.