Mitochondrial calcium (mtCa²⁺) uptake via the mitochondrial calcium uniporter (MCU) couples calcium homeostasis and energy metabolism. mtCa²⁺ uptake via MCU is rate-limiting for mitochondrial activation during muscle contraction, but its pathophysiological role and therapeutic application remain largely uncharacterized. By profiling human muscle biopsies, patient-derived myotubes, and preclinical models, we discovered a conserved downregulation of mitochondrial calcium uniporter regulator 1 (MCUR1) during skeletal muscle aging that associates with human sarcopenia and impairs mtCa²⁺ uptake and mitochondrial respiration. Through a screen of 5,000 bioactive molecules, we identify the natural polyphenol oleuropein as a specific MCU activator that stimulates mitochondrial respiration via mitochondrial calcium uptake 1 (MICU1) binding. Oleuropein activates mtCa²⁺ uptake and energy metabolism to enhance endurance and reduce fatigue in young and aged mice but not in muscle-specific MCU knockout (KO) mice. Our work demonstrates that impaired mtCa²⁺ uptake contributes to mitochondrial dysfunction during aging and establishes oleuropein as a novel food-derived molecule that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.

中文翻译：

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线粒体钙的摄取量在衰老过程中下降，并被橄榄苦苷直接激活，以促进能量代谢和骨骼肌性能


线粒体钙单向转运蛋白 （MCU） 对线粒体钙 （mtCa²⁺） 的摄取将钙稳态和能量代谢相结合。通过 MCU 摄取 mtCa²⁺ 对肌肉收缩过程中线粒体活化的速率有限制，但其病理生理作用和治疗应用在很大程度上仍未得到表征。通过分析人体肌肉活检、患者来源的肌管和临床前模型，我们发现在骨骼肌衰老过程中线粒体钙单向转运蛋白调节因子 1 （MCUR1） 的保守下调与人类肌肉减少症相关，并损害 mtCa²⁺ 摄取和线粒体呼吸。通过筛选 5,000 个生物活性分子，我们将天然多酚橄榄苦苷确定为一种特定的 MCU 激活剂，通过线粒体钙摄取 1 （MICU1） 结合刺激线粒体呼吸。橄榄苦苷激活 mtCa²⁺ 摄取和能量代谢，以增强年轻和老年小鼠的耐力并减少疲劳，但不会激活肌肉特异性 MCU 敲除 （KO） 小鼠。我们的工作表明，mtCa²⁺ 摄取受损会导致衰老过程中的线粒体功能障碍，并将橄榄苦苷确立为一种新型食物衍生分子，专门针对 MCU 以刺激线粒体生物能量学和肌肉性能。