Mito-SEP MOCCI and miR-147b from C15ORF48 coordinate to provide host protection during acute infection

Mito-SEPs are peptides that localize to the mitochondria to regulate oxidative metabolism. To identify mito-SEPs that promote resolution of inflammation, we performed a proteo-genomic mito-SEP screen in IL-1b-treated human aortic endothelial cells . We discovered MOCCI (Modulator of Cytochrome C oxidase during Inflammation), an Interleukin-1b-induced mito-SEP encoded by the C15ORF48 gene. MOCCI is a paralog of NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 4 (NDUFA4), the 14th subunit of the mitochondrial respiratory chain Complex IV (CIV). During inflammation, MOCCI displaces NDUFA4 in CIV, aided by repression of NDUFA4 mRNA by miR-147b encoded within the 3 untranslated region of C15ORF48. MOCCI lowers membrane potential and ROS production with overall cyto-protective and anti-inflammatory effects. In parallel, miR-147b exerts a strong anti-viral effect by enhancing RIG-I/MDA-5 pathway of viral recognition and induction of the interferon response. Our findings demonstrate how the coding and non-coding functions of C15ORF48 coordinate to regulate the composition and activity of Complex IV to limit pathogen replication and host inflammation during acute infection.