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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\u2010activated receptor \u03b3 coactivator 1\u03b1 (PGC\u20101\u03b1) in mHTT\u2010expressing cells. The\u00a0PGC\u20101\u03b1 increase was accompanied by the increment of mitochondrial mass and by the rebalancing of mitochondrial dynamics with a promotion of the mitochondrial fusion. Meldonium\u2010induced PGC\u20101\u03b1 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\u20101\u03b1, as a master coregulator of mitochondrial biogenesis, energy homeostasis, and antioxidant defense, is a potential therapeutic target in HD.<\/jats:p>","DOI":"10.1002\/jcp.27602","type":"journal-article","created":{"date-parts":[[2018,10,26]],"date-time":"2018-10-26T10:53:39Z","timestamp":1540551219000},"page":"9233-9246","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Meldonium improves Huntington\u2019s disease mitochondrial dysfunction by restoring peroxisome proliferator\u2010activated receptor \u03b3 coactivator 1\u03b1 expression"],"prefix":"10.1002","volume":"234","author":[{"given":"Francesca","family":"Di Cristo","sequence":"first","affiliation":[{"name":"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 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