The epithelial <i>C15ORF48/miR-147-NDUFA4</i> axis is an essential regulator of gut inflammation, energy metabolism, and the microbiome.

Abstract

Chronic inflammation is epidemiologically linked to the pathogenesis of gastrointestinal diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). However, our understanding of the molecular mechanisms controlling gut inflammation remains insufficient, hindering the development of targeted therapies for IBD and CRC. In this study, we uncovered <i>C15ORF48/miR-147</i> as a negative regulator of gut inflammation, operating through the modulation of epithelial cell metabolism. <i>C15ORF48/miR-147</i> encodes two molecular products, C15ORF48 protein and miR-147-3p microRNA, which are predominantly expressed in the intestinal epithelium. <i>C15ORF48/miR-147</i> ablation leads to gut dysbiosis and exacerbates chemically induced colitis in mice. C15ORF48 and miR-147-3p work together to suppress colonocyte metabolism and inflammation by silencing <i>NDUFA4</i>, a subunit of mitochondrial complex IV (CIV). Interestingly, the C15ORF48 protein, a structural paralog of NDUFA4, contains a unique C-terminal α-helical domain crucial for displacing NDUFA4 from CIV and its subsequent degradation. <i>NDUFA4</i> silencing hinders NF-κB signaling activation and consequently attenuates inflammatory responses. Collectively, our findings have established the <i>C15ORF48/miR-147</i>-<i>NDUFA4</i> molecular axis as an indispensable regulator of gut homeostasis, bridging mitochondrial metabolism and inflammation.