瑞士洛桑联邦理工学院Umberto De Marchi等研究人员合作发现，线粒体钙离子摄取在衰老过程中下降，并直接被橄榄苦苷激活来促进能量代谢和骨骼肌性能。2024年11月26日，国际知名学术期刊《细胞—代谢》在线发表了这一成果。

通过分析人类肌肉活检、患者衍生的肌管以及临床前模型，研究人员发现骨骼肌衰老过程中线粒体钙离子单通道调节因子1（MCUR1）下调，且这一变化与人类肌肉萎缩症相关，损害了线粒体钙离子（mtCa²⁺）的摄取和线粒体呼吸。

通过筛选5000种生物活性分子，研究人员发现天然多酚橄榄苦苷作为一种特异性线粒体钙离子单通道（MCU）激活剂，能通过与线粒体钙离子摄取1（MICU1）结合来刺激线粒体呼吸。橄榄苦苷激活mtCa²⁺摄取和能量代谢，增强年轻和衰老小鼠的耐力并减少疲劳，但在肌肉特异性MCU基因敲除（KO）小鼠中没有效果。

该研究表明，mtCa²⁺摄取受损是衰老过程中线粒体功能障碍的一个因素，并确立了橄榄苦苷作为一种新型食物来源分子，能特异性靶向MCU，刺激线粒体生物能学和肌肉性能。

研究人员表示，mtCa²⁺摄取通过MCU连接钙稳态与能量代谢。通过MCU进行的mtCa2+摄取是肌肉收缩过程中线粒体激活的限速步骤，但其病理生理作用和治疗应用尚未得到充分研究。

附：英文原文

Title: Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance

Author: Gaia Gherardi, Anna Weiser, Flavien Bermont, Eugenia Migliavacca, Benjamin Brinon, Guillaume E. Jacot, Aurélie Hermant, Mattia Sturlese, Leonardo Nogara, Filippo Vascon, Agnese De Mario, Andrea Mattarei, Emma Garratt, Mark Burton, Karen Lillycrop, Keith M. Godfrey, Laura Cendron, Denis Barron, Stefano Moro, Bert Blaauw, Rosario Rizzuto, Jerome N. Feige, Cristina Mammucari, Umberto De Marchi

Issue&Volume: 2024-11-26

Abstract: 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.

DOI: 10.1016/j.cmet.2024.10.021

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00417-0