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

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.

The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure-Based Virtual Screening to In Vivo Biological Activity

“…To confirm the efficacy of newly synthesized compounds in vivo, the selected compounds were tested in a Drosophila model of HD, with transgenic flies that express full-length human pathogenic cDNA, encoding a mutated HTT protein [ 9 , 24 ]. The expression of this construct in the transgenic fly recapitulated the majority of the pathological hallmarks of HD, including early death and locomotor dysfunction.…”

“…The expression of this construct in the transgenic fly recapitulated the majority of the pathological hallmarks of HD, including early death and locomotor dysfunction. In a recent previous work, Di Cristo et al reported that THP significantly improved the lifespan and motor function in this HD fly and that the srl gene (DmPGC1-alpha) was involved in those effects [ 9 ]. In this work, we wanted to evaluate the lifespan and motor dysfunction of Q128HD-FL flies after treatment with the THP-derived molecules.…”

“…The cells expressed endogenous levels of normal and mutant full-length huntingtin protein with seven (wild-type STHdh Q7/7 ) and 111 (STHdh Q111/111 ) glutamines, respectively. Striatal cells were grown as described by Di Cristo et al [ 9 ].…”

“…In THP-induced low-carnitine cells, THP diminishes β-oxidation by inhibiting fatty acid (FA) transport into the mitochondrial matrix [ 5 ] and modulates the energy metabolism by increasing glycolysis [ 6 , 7 , 8 ]. Recently, we demonstrated that THP was able to effectively restore the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a master regulator of mitochondria biogenesis, dynamics, and oxidative metabolism, in cell and animal models of Huntington’s disease (HD) [ 9 , 10 ].…”

Exaggerated mitophagy: a weapon of striatal destruction in the brain?

“…Severe loss of mitochondrial activities, such as reduction in the activities of complex II/III and aconitase, was found in postmortem samples of the caudate/putamen in HD patients [15]. However, defects in mitochondrial mass are not very common in HD animal models and were found only in selected models [16][17][18].…”