Bacterial muropeptides promote OXPHOS and suppress mitochondrial stress in normal and human mitochondrial disease models

Mitochondrial dysfunction critically contributes to many major human diseases but effective therapeutic methods to combat mitochondrial dysfunction are lacking 1,2 . Mitochondria of animal cells are sites of interaction between gut microbial metabolites and host factors, and many such interactions may be beneficial to mitochondrial health and host physiology 3 , albeit that specific beneficial interactions and the underlying mechanisms remain to be uncovered. Here we report the role of muropeptides derived from bacterial cell wall peptidoglycan (PG) in promoting mitochondrial functions in mammalian models. We found that muropeptides directly bind to ATP synthase, which stabilizes the complex and promotes its activity. The benefit is seen in increased oxidative respiration and mitochondrial membrane potential, as well as decreased oxidative stress in human intestinal epithelial cells (IECs). Strikingly, we also found that muropeptide treatment can recover mitochondrial structure and functions, as well as inhibit several pathological phenotypes of mutant fibroblast cells derived from mitochondrial disease patients. In mice, we show muropeptides accumulate in mitochondria of IECs and promote small intestinal homeostasis and nutrient absorption by modulating energy metabolism. This study identifies ATP synthase as a muropeptide receptor and the corresponding physiological function in mammals, and points to a potential treatment for human mitochondrial dysfunction diseases. Highlights Bacterial muropeptides bind and stabilize ATP synthase complex and enhance its activity Muropeptides enhance mitochondrial OXPHOS in human IECs Muropeptides recover mitochondrial structure and functions in mitochondrial disease cells Muropeptides promote small intestinal epithelial homeostasis and nutrient uptake in mice