SUMMARYMitochondrial calcium (mtCa2+) uptake via the Mitochondrial Calcium Uniporter (MCU) couples the regulation of calcium homeostasis to energy production. mtCa2+uptake is rate-limiting for mitochondrial activation during muscle contraction, but how MCU is affected during physiopathology and whether it can be stimulated therapeutically remains largely uncharacterized. By profiling human and preclinical aging of skeletal muscle, we discovered a conserved down-regulation of MCUR1 during aging that decreases mtCa2+uptake and drives sarcopenia. Through a screen of 5000 bioactive nutrients, we identify the natural polyphenol Oleuropein as a specific MCU activator that stimulates mitochondrial respiration via binding to MICU1. Oleuropein activates mtCa2+uptake and oxidative energy metabolism to enhance endurance and limit fatigue in vivo both in young and aged. These effects of Oleuropein are mediated by an MCU-dependent mechanism in skeletal muscle as they are lost upon muscle-specific MCU KO. Our work demonstrates that impaired mtCa2+uptake causes mitochondrial dysfunction during aging and establishes Oleuropein as a novel nutrient that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.
