Progerin disrupts intestinal epithelial homeostasis by impairing mitochondrial metabolism and absorptive enterocyte maturation
- 1Institut Necker Enfants Malades
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.
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BibTeX
@misc{reisacher2026progerin,
title = {{Progerin disrupts intestinal epithelial homeostasis by impairing mitochondrial metabolism and absorptive enterocyte maturation}},
author = {C. Reisacher and M. Singh and L. Arbibe},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.09.758066},
url = {https://www.biorxiv.org/content/10.64898/2026.10.09.758066v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Progerin disrupts intestinal epithelial homeostasis by impairing mitochondrial metabolism and absorptive enterocyte maturation
AU - C. Reisacher
AU - M. Singh
AU - L. Arbibe
PY - 2026
DA - 2026/10/09
PB - bioRxiv
DO - 10.64898/2026.10.09.758066
UR - https://www.biorxiv.org/content/10.64898/2026.10.09.758066v1
AB - 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.
ER -