Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance
Mitochondrial calcium (mtCa<sup>2+</sup>) uptake via the mitochondrial calcium uniporter (MCU) couples calcium homeostasis and energy metabolism. mtCa<sup>2+</sup> 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 mtCa<sup>2+</sup> 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 mtCa<sup>2+</sup> 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 mtCa<sup>2+</sup> 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.
Authors
- Guillaume Jacot (ORCID: https://orcid.org/0000-0001-5821-2717)
- Umberto De Marchi
- Stefano Moro (ORCID: https://orcid.org/0000-0002-7514-3802)
- Eugenia Migliavacca (ORCID: https://orcid.org/0000-0003-1883-1972)
- Rosario Rizzuto (ORCID: https://orcid.org/0000-0001-7044-5097)
- Laura Cendron (ORCID: https://orcid.org/0000-0002-0125-0461)
- Karen A. Lillycrop (ORCID: https://orcid.org/0000-0001-7350-5489)
- Keith M. Godfrey (ORCID: https://orcid.org/0000-0002-4643-0618)
- Jérôme N. Feige (ORCID: https://orcid.org/0000-0002-4751-264X)
- Aurélie Hermant
- Bert Blaauw (ORCID: https://orcid.org/0000-0002-4167-5106)
- Emma Garratt (ORCID: https://orcid.org/0000-0001-5268-4203)
- Flavien Bermont
- Benjamin Brinon
- Gaia Gherardi (ORCID: https://orcid.org/0000-0001-6212-3477)
- Agnese De Mario (ORCID: https://orcid.org/0000-0001-5129-4780)
- Filippo Vascon (ORCID: https://orcid.org/0000-0002-5747-507X)
- Leonardo Nogara (ORCID: https://orcid.org/0000-0002-7009-8707)
- Andrea Mattarei (ORCID: https://orcid.org/0000-0002-2023-0749)
- Denís Barron (ORCID: https://orcid.org/0000-0002-1525-405X)
- Cristina Mammucari (ORCID: https://orcid.org/0000-0003-3220-9610)
- Anna Weiser (ORCID: https://orcid.org/0000-0002-6433-024X)
- Mark A. Burton (ORCID: https://orcid.org/0000-0002-7117-8151)
- Mattia Sturlese (ORCID: https://orcid.org/0000-0003-3944-0313)
Institutions
- University of Padua (IT)
- University Hospital Southampton NHS Foundation Trust (GB)
- Veneto Institute of Molecular Medicine (IT)
- Nestlé (Switzerland) (CH)
- NIHR Southampton Biomedical Research Centre (GB)
- University of Southampton (GB)
- École Polytechnique Fédérale de Lausanne (CH)
Publication Details
- Journal
- Cell Metabolism
- Published
- 2024-11-26
- DOI
- https://doi.org/10.1016/j.cmet.2024.10.021
- Citations
- 48
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 11.22
Funders
- Muscular Dystrophy Association
- National Institute for Health and Care Research
- European Commission
- Ministero della Salute
- Università degli Studi di Padova
- AFM-Téléthon
- Regione del Veneto
- National Institute for Health Research Southampton Biomedical Research Centre
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Agenzia Italiana del Farmaco, Ministero della Salute
- European Regional Development Fund