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J Cell Physiol. 2019 Jun;234(6):9233-9246. doi: 10.1002/jcp.27602. Epub 2018 Oct 26.

Meldonium improves Huntington's disease mitochondrial dysfunction by restoring peroxisome proliferator-activated receptor γ coactivator 1α expression.

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Department of Medical, Surgical, Neurological, Metabolic Sciences, and Aging, 2nd Division of Neurology, Center for Rare Diseases and InterUniversity Center for Research in Neurosciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
Institute of Bioscience and BioResources (IBBR), National Research Council (CNR), Naples, Italy.
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
Institute for Cell and Molecular Bioscience, Campus for Ageing and Vitality, University of Newcastle, Newcastle-upon-Tyne, United Kingdom.
Department of Science, University of Basilicata, Potenza, Italy.
Department of Experimental Medicine, Biotechnology and Molecular Biology Section, University of Campania "Luigi Vanvitelli, Naples, Italy.
Department of Biology, Center for Biotechnology, College of Science and Technology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, Pennsylvania.
Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
Institute of Agro-environmental and Forest Biology (IBAF), National Research Council (CNR), Naples, Italy.


Mitochondrial dysfunction seems to play a fundamental role in the pathogenesis of neurodegeneration in Huntington's disease (HD). We assessed possible neuroprotective actions of meldonium, a small molecule affecting mitochondrial fuel metabolism, in in vitro and in vivo HD models. We found that meldonium was able to prevent cytotoxicity induced by serum deprivation, to reduce the accumulation of mutated huntingtin (mHtt) aggregates, and to upregulate the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in mHTT-expressing cells. The PGC-1α increase was accompanied by the increment of mitochondrial mass and by the rebalancing of mitochondrial dynamics with a promotion of the mitochondrial fusion. Meldonium-induced PGC-1α significantly alleviated motor dysfunction and prolonged the survival of a transgenic HD Drosophila model in which mHtt expression in the nervous system led to progressive motor performance deficits. Our study strongly suggests that PGC-1α, as a master coregulator of mitochondrial biogenesis, energy homeostasis, and antioxidant defense, is a potential therapeutic target in HD.


Huntington; meldonium; mitochondrial dysfunction; neurodegeneration


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