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

Gaia Gherardi¹, Anna Weiser², Flavien Bermont³, Eugenia Migliavacca³, Benjamin Brinon³, Guillaume E Jacot³, Aurélie Hermant³, Mattia Sturlese⁴, Leonardo Nogara⁵, Filippo Vascon⁶, Agnese De Mario¹, Andrea Mattarei⁴, Emma Garratt⁷, Mark Burton⁸, Karen Lillycrop⁹, Keith M Godfrey¹⁰, Laura Cendron⁶, Denis Barron³, Stefano Moro⁴, Bert Blaauw¹¹, Rosario Rizzuto¹², Jerome N Feige¹³, Cristina Mammucari¹⁴, Umberto De Marchi¹⁵

Affiliations

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.

PMID: 39603237
DOI: 10.1016/j.cmet.2024.10.021

Free article

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

Gaia Gherardi et al. Cell Metab. 2025.

Free article

. 2025 Feb 4;37(2):477-495.e11.

doi: 10.1016/j.cmet.2024.10.021. Epub 2024 Nov 26.

Authors

Affiliations

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.

PMID: 39603237
DOI: 10.1016/j.cmet.2024.10.021

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.

Keywords: MCU; MCUR1; aging; calcium signaling; endurance; energy; fatigue; mitochondria; polyphenols; sarcopenia; skeletal muscle.

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Conflict of interest statement

Declaration of interests The authors A.W., F.B., B. Brinon, G.E.J., A.H., E.M., D.B., J.N.F., and U.D.M. are employees of Nestlé Research, which is part of the Société des Produits Nestlé SA (SPN). SPN has filed patents on the use of oleuropein for muscle and mitochondrial health. K.M.G. has received reimbursement for speaking at conferences sponsored by companies selling nutritional products and is part of an academic consortium that has received research funding from Bayer, Société des Produits Nestlé SA, BenevolentAI Bio Ltd., and Danone.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials