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

Lookup NU author(s): Dr Filippo Scialo

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Abstract

© 2018 Wiley Periodicals, Inc. 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.


Publication metadata

Author(s): Di Cristo F, Finicelli M, Digilio FA, Paladino S, Valentino A, Scialo F, D'Apolito M, Saturnino C, Galderisi U, Giordano A, Melone MAB, Peluso G

Publication type: Article

Publication status: Published

Journal: Journal of Cellular Physiology

Year: 2019

Volume: 234

Issue: 6

Pages: 9233-9246

Print publication date: 01/06/2019

Online publication date: 26/10/2018

Acceptance date: 19/09/2018

ISSN (print): 0021-9541

ISSN (electronic): 1097-4652

Publisher: Wiley-Liss Inc.

URL: https://doi.org/10.1002/jcp.27602

DOI: 10.1002/jcp.27602


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