Age‐associated mitochondrial complex I deficiency is linked to increased stem cell proliferation rates in the mouse colon

One of the hallmarks of aging is an accumulation of cells with defects in oxidative phosphorylation (OXPHOS) due to mutations of mitochondrial DNA (mtDNA). Rapidly dividing tissues maintained by stem cells, such as the colonic epithelium, are particularly susceptible to accumulation of OXPHOS defects over time; however, the effects on the stem cells are unknown. We have crossed a mouse model in which intestinal stem cells are labelled with EGFP (Lgr5‐EGFP‐IRES‐creERT2) with a model of accelerated mtDNA mutagenesis (PolgAmut/mut) to investigate the effect of OXPHOS dysfunction on colonic stem cell proliferation. We show that a reduction in complex I protein levels is associated with an increased rate of stem cell cycle re‐entry. These changes in stem cell homeostasis could have significant implications for age‐associated intestinal pathogenesis. Age‐associated mitochondrial DNA mutations accumulate in the colonic epithelial crypts of the PolgAmut/mut and PolgA+/mut mice. This leads to a reduction in mitochondrial complex I and IV protein levels. Stem cells with complex I defects re‐enter the cell cycle 20% more frequently than those with normal complex I levels.