Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance.
1. Cell Metab. 2025 Feb 4;37(2):477-495.e11. doi: 10.1016/j.cmet.2024.10.021. Epub 2024 Nov 26. Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance. Gherardi G(1), Weiser A(2), Bermont F(3), Migliavacca E(3), Brinon B(3), Jacot GE(3), Hermant A(3), Sturlese M(4), Nogara L(5), Vascon F(6), De Mario A(1), Mattarei A(4), Garratt E(7), Burton M(8), Lillycrop K(9), Godfrey KM(10), Cendron L(6), Barron D(3), Moro S(4), Blaauw B(11), Rizzuto R(12), Feige JN(13), Mammucari C(14), De Marchi U(15). Author information: (1)Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy. (2)Nestlé Institute of Health Sciences, Nestlé Research, Société des Produit Nestlé S.A., EPFL Innovation Park, 1015 Lausanne, Switzerland; Molecular Nutritional Medicine, Else Kröner Fresenius Center for Nutritional Medicine, Technische Universität München, 85354 Freising, Germany. (3)Nestlé Institute of Health Sciences, Nestlé Research, Société des Produit Nestlé S.A., EPFL Innovation Park, 1015 Lausanne, Switzerland. (4)Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy. (5)Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy. (6)Department of Biology, University of Padova, 35131 Padova, Italy. (7)Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK; NIHR Southampton Biomedical Research Centre, University of Southampton & University Hospital Southampton NHS Foundation Trust, Southampton, UK. (8)Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK. (9)Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK; NIHR Southampton Biomedical Research Centre, University of Southampton & University Hospital Southampton NHS Foundation Trust, Southampton, UK; Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK. (10)Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK; NIHR Southampton Biomedical Research Centre, University of Southampton & University Hospital Southampton NHS Foundation Trust, Southampton, UK; Medical Research Council Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK. (11)Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy. (12)Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Myology Center (CIR-Myo), University of Padova, 35131 Padova, Italy. Electronic address: rosario.rizzuto@unipd.it. (13)Nestlé Institute of Health Sciences, Nestlé Research, Société des Produit Nestlé S.A., EPFL Innovation Park, 1015 Lausanne, Switzerland; School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. Electronic address: jerome.feige@rd.nestle.com. (14)Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Myology Center (CIR-Myo), University of Padova, 35131 Padova, Italy. Electronic address: cristina.mammucari@unipd.it. (15)Nestlé Institute of Health Sciences, Nestlé Research, Société des Produit Nestlé S.A., EPFL Innovation Park, 1015 Lausanne, Switzerland. Electronic address: umberto.demarchi@rd.nestle.com. 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 bioe