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

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

doi:10.1016/j.cmet.2024.10.021

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

Cell Metab. 2025 Feb 4;37(2):477-495.e11. doi: 10.1016/j.cmet.2024.10.021. Epub 2024 Nov 26.

Authors

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

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.

MeSH terms

Aging* / metabolism
Animals
Calcium Channels / metabolism
Calcium* / metabolism
Energy Metabolism* / drug effects
Female
Humans
Iridoid Glucosides / pharmacology
Iridoids* / pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria* / drug effects
Mitochondria* / metabolism
Mitochondria, Muscle* / drug effects
Mitochondria, Muscle* / metabolism
Muscle, Skeletal* / drug effects
Muscle, Skeletal* / metabolism
Sarcopenia / metabolism

Substances

oleuropein
Iridoid Glucosides
Calcium
Iridoids
Calcium Channels
mitochondrial calcium uniporter