Meldonium improves Huntington's disease mitochondrial dysfunction by restoring peroxisome proliferator‐activated receptor γ coactivator 1α expression. Issue 6 (26th October 2018)

• Record Type: Journal Article
• Authors: Di Cristo, Francesca; Finicelli, Mauro; Digilio, Filomena Anna; Paladino, Simona; Valentino, Anna; Scialò, Filippo; D'Apolito, Maria; Saturnino, Carmela; Galderisi, Umberto; Giordano, Antonio; Melone, Mariarosa Anna Beatrice; Peluso, Gianfranco
• Is Part Of: Journal of cellular physiology. Volume 234:Issue 6(2019:Jun.)
• Page Start: 9233
• Page End: 9246
• Publication Date: 2018-10-26
• Subjects: Huntington -- meldonium -- mitochondrial dysfunction -- neurodegeneration; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.27602
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: 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. Abstract : The transcriptional coactivator peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α) pathway results impaired in Huntington's disease (HD). Meldonium, through PGC‐1α modulation, was able to reduce mutated huntingtin aggregates and to improve the mitochondrial dysfunction in mutated huntingtin (mHTT)‐expressing cells, as well as to alleviate motor dysfunction and to extend survival in a transgenic HD Drosophila model.