Mitochondrial DNA mutation triggers early-onset intestinal epithelial cell dysfunction during acute colitis [scRNA-Seq]

However, the mechanism underlying the selection against mutant mtDNA and the impact of pathogenic mtDNA mutations on intestinal epithelial cells (IECs) remain unclear. Here, we employed mitochondrial single-cell assay for transposase-accessible chromatin with sequencing (mtscATAC-seq) to examine the heteroplasmy of IECs in m.G5081A (mt-tRNA) and m.G12918A (mt-mRNA) mutant mouse models over a two-year lifespan.

Our findings reveal age-dependent purifying selection against mutant mtDNA across nine IEC subtypes, a process originating in intestinal stem cells (ISCs) that does not strengthen during cellular differentiation. Combining the analysis of single-cell RNA sequencing, we found that young mice with high m.G5081A mutation loads exhibit IEC dysfunction, including impaired enterocyte differentiation and defective Paneth cell granule formation.