UPAP attenuates renal fibrosis by modulating mitochondrial unfolded protein response via HSP60-ClpP complex

Abstract

Renal fibrosis is a common pathological pathway of chronic kidney disease (CKD). However, specific treatments to slow or halt renal fibrosis are still lacking. Microproteins encoded by small open reading frames (sORFs) within long non-coding RNAs (lncRNAs) have been increasingly identified, yet the biological function of most microproteins remains unknown. Here, we identified a renal fibrosis-associated noncanonical sORF derived from AC103718.1. This noncanonical sORF encodes an unannotated 101-amino acid protein, designated UPAP (mitochondrial unfolded protein response-associated microprotein). UPAP was significantly downregulated in human fibrotic kidney tissues, with expression negatively correlated with the extent of tubulointerstitial fibrosis and the decline in renal function. CRISPR/Cas9-mediated UPAP knockout promotes the imbalance of mitochondrial proteostasis and renal fibrosis in renal tubular epithelial cells. In two murine models of renal fibrosis, administration of exogenous UPAP markedly attenuated renal fibrosis, indicating that UPAP has therapeutic value. Mechanistically, UPAP localizes to the inner mitochondrial membrane, where it forms a complex with HSP60 and ClpP, enhancing their interaction to activate the mitochondrial unfolded protein response (UPRmt) and maintain mitochondrial proteostasis during renal fibrosis. Disruption of HSP60-ClpP interaction by small-molecule inhibitor DCEM1 abolish the protective antifibrotic effect of UPAP overexpression. Our findings systematically elucidate the biological function of UPAP in modulating UPRmt, thereby providing a promising, mechanism-backed therapeutic strategy for the treatment of renal fibrosis.

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