Progerin disrupts intestinal epithelial homeostasis by impairing mitochondrial metabolism and absorptive enterocyte maturation

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a segmental premature ageing disease that predominantly affects tissues with high regenerative capacity. Although the intestine is the most rapidly self-renewing tissue of adult mammals, it has so far been considered only as a source of microbiota-derived disturbances in progeria, and whether the intestinal epithelium is itself a target of progerin remains unknown. Here, using the LmnaG609G/G609G and LmnaG609G/+ mouse models, intestinal organoids and single-cell RNA sequencing, we show that progerin is expressed in colonic enterocytes and in SMA+ subepithelial myofibroblasts of the stem-cell niche. Heterozygous progeria mice develop increased intestinal permeability from 30 weeks of age, reaching levels reported in physiologically aged (>20-month-old) mice. Progeria-derived intestinal organoids display reduced mitochondrial oxygen consumption, a compensatory increase in glycolysis and impaired crypt budding. Single-cell transcriptomics of the colonic epithelium and lamina propria revealed that, while lineage composition is preserved, progerin induces a coordinated reprogramming characterised by repression of oxidative phosphorylation and mitochondrial quality-control genes, including Nod2, activation of interferon, TNF-NF-kB and innate defence programs, and up-regulation of RNA-processing and chromatin-associated pathways. Trajectory analysis showed that progeria absorptive enterocytes selectively fail to reach terminal differentiation states and retain progenitor-like WNT, NOTCH and EGFR signatures, while lacking the mitochondrial programs required for maturation. Together, these findings identify the intestinal epithelium as a cell-intrinsic target of progerin and support a model in which mitochondrial insufficiency stalls absorptive enterocyte maturation and weakens the intestinal barrier, recapitulating, prematurely, key features of colon ageing.