Mitochondria regulate Drosophila intestinal stem cell differentiation through FOXO

Stem cells often rely on glycolysis for energy production, and switching to oxidative phosphorylation is believed to be essential for their differentiation. To explore the link between mitochondrial respiration and stem cell differentiation, we genetically disrupted electron transport chain (ETC) complexes in the intestinal stem cells (ISCs) of Drosophila. We found that ISCs carrying impaired ETC proliferated much more slowly than normal, produced very few intestinal progenitors, or enteroblasts, and failed to differentiate into enterocytes or enteroendocrine cells. One of the main impediments to ISCs differentiation appeared to be abnormally elevated forkhead box O (FOXO) signaling in the ETC-deficient ISCs, as genetically suppressing the signaling pathway partially rescued the differentiation defect. Contrary to common belief, neither reactive oxygen species (ROS) accumulation nor adenosine triphosphate (ATP) reduction appeared to mediate the ETC mutant phenotype. Our results demonstrate that ETC is essential for Drosophila ISC proliferation and differentiation in vivo, and acts at least partially by repressing endogenous FOXO signaling. They also raise the possibility that ETC complexes have a role in stem cell differentiation beyond electron transfer and ATP production.