Long noncoding RNA uc173 is a novel regulator of mitochondrial metabolism driving intestinal mucosal growth.

Abstract

Background & aims: Long noncoding RNA uc.173, transcribed from ultraconserved regions, modulates many cell processes central to human pathologies, but the mechanism underlying uc.173 in the homeostasis of the intestinal epithelium is underexplored. Here we investigated the role of uc.173 in regulating mitochondrial metabolism and defined the implication of altered mitochondrial activity by uc.173 in renewal of the intestinal mucosa.

Methods: Studies were conducted in CRISPR-Cas9 knock-in mice, primary enterocytes, and Caco-2 cells. Mitochondrial structure and function were elucidated by measuring mitochondria-associated proteins and mitochondrial respiratory capacity. Intestinal mucosal growth was measured by Ki67 immunostaining or BrdU incorporation assays.

Results: Transient and specific deletion of uc.173 in the intestinal epithelium of mice by CRISPR-Cas9 knock-in using small guide RNA decreased the levels of several mitochondria-associated proteins including PGC-1α, along with disrupted mucosal growth. Decreasing the levels of uc.173 in cultured intestinal epithelial cells also decreased mitochondrial proteins and caused defects in the mitochondrial respiratory capacity. Reinforcing mitochondrial activity by using a mitochondrial activator or by overexpressing PGC-1α rescued growth of uc.173-deficient intestinal organoids. Mechanistic studies revealed that uc.173 increased PGC-1α expression by acting as a molecular decoy for miR-29b, thereby preventing the repressive interaction of miR-29b with PGC-1α mRNA.

Conclusions: These findings indicate that uc.173 is a novel regulator of mitochondrial metabolism in the intestinal epithelium and highlight a role of deregulation of uc.173, miR-29b, and PGC-1α in the suppressed renewal of intestinal mucosa in patients with critical illnesses.