Mitochondrial dysfunction, a hallmark of aging, underlies physiological decline and chronic diseases, including sarcopenia, a condition marked by reduced muscle mass, strength, and functionality. While exercise and nutrition offer partial protection, direct therapeutic interventions targeting mitochondrial health remain unexplored. A recent study published in Cell Metabolism identifies oleuropein, a polyphenol derived from olives, as a novel mitochondrial calcium uniporter (MCU) activator that boosts mitochondrial function and combats muscle aging.
Mitochondrial calcium (mtCa²⁺) uptake is essential for skeletal muscle energy production during contraction, regulated by the MCU complex. This process drives oxidative metabolism and adenosine triphosphate (ATP) synthesis. However, aging impairs mitochondrial function, reducing mtCa²⁺ uptake and contributing to sarcopenia. The study highlights the role of mitochondrial calcium uniporter regulator 1 (MCUR1), a critical component of the MCU complex, in maintaining mtCa²⁺ homeostasis. A decline in MCUR1 expression was found to directly correlate with impaired muscle performance and mitochondrial bioenergetics in aged and sarcopenic individuals.
Gherardi and colleagues analyzed skeletal muscle transcriptomics using RNA sequencing data from older individuals with and without sarcopenia, sourced from the Singapore Sarcopenia Study. They identified significant downregulation of genes involved in mtCa²⁺ uptake, particularly MCUR1. In primary human myotubes derived from aged donors, mtCa²⁺ uptake was reduced by 45%, with even greater reductions observed in sarcopenic individuals. This decline impaired mitochondrial respiration and shifted metabolic reliance toward fatty acid oxidation, indicative of dysfunctional energy metabolism.
López-Otín et al. identified mitochondrial dysfunction as a key factor in age-related decline, with impaired biogenesis and energy production leading to oxidative damage. Their study found that MCUR1 knockdown in young myotubes mimicked aging-related mitochondrial deficits, while MCUR1 overexpression restored mitochondrial function. In aged murine models, reduced MCUR1 expression led to a 54% decline in mitochondrial calcium uptake, which was reversed by restoring MCUR1 or activating pyruvate dehydrogenase (PDH). High-throughput screening revealed oleuropein as a potent activator of mitochondrial calcium uptake, enhancing mitochondrial energy production and exercise performance in human myotubes and murine models. Oleuropein also reversed age-related mitochondrial decline, improving muscle strength and reducing fatigue in both aged human myotubes and sarcopenic rodents.
Oleuropein acts rapidly and specifically on the MCU complex, transiently elevating mtCa²⁺ levels, activating PDH dephosphorylation, and boosting ATP production. Preclinical studies confirm its efficacy in restoring mitochondrial respiration, improving exercise performance, and reversing sarcopenia-related muscle decline. Its safety profile and bioenergetic benefits make it a promising candidate for therapeutic interventions targeting age-related muscle dysfunction, with further clinical trials needed to validate these findings. This study highlights the critical role of mitochondrial calcium uptake in muscle health and aging, offering hope for developing targeted therapies to improve the quality of life in aging populations.
References
- Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance – ScienceDirect [Internet]. [cited 2024 Dec 3]. Available from: https://www.sciencedirect.com/science/article/pii/S1550413124004170?via%3Dihub
- López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The Hallmarks of Aging. Cell. 2013 Jun 6;153(6):1194–217.