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Meldonium improves Huntington's disease mitochondrial dysfunction by restoring peroxisome proliferator-activated
Francesca Di Cristo1, Mauro Finicelli2, Filomena Anna Digilio2
1Department 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.
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.
Insights
Meldonium shows neuroprotective effects in Huntington's disease (HD) models by improving mitochondrial function and boosting PGC-1α. This suggests PGC-1α as a therapeutic target for HD, potentially alleviating motor deficits and extending survival.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Pharmacology
Background:
- Mitochondrial dysfunction is a key factor in Huntington's disease (HD) pathogenesis.
- Huntington's disease is a neurodegenerative disorder characterized by motor deficits and progressive neuronal loss.
Purpose of the Study:
- To investigate the neuroprotective potential of meldonium, a mitochondrial fuel metabolism modulator, in Huntington's disease models.
- To explore the role of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in meldonium's therapeutic effects.
Main Methods:
- In vitro assays using mutated huntingtin (mHtt)-expressing cells to assess cytotoxicity and aggregate formation.
- In vivo studies using a transgenic Huntington's disease Drosophila model.
- Measurement of PGC-1α expression, mitochondrial mass, and dynamics.
Main Results:
- Meldonium prevented serum deprivation-induced cytotoxicity and reduced mHtt aggregate accumulation in vitro.
- Meldonium upregulated PGC-1α expression, increasing mitochondrial mass and promoting mitochondrial fusion.
- Meldonium treatment alleviated motor dysfunction and extended survival in a Drosophila model of HD.
Conclusions:
- Meldonium exhibits significant neuroprotective effects in Huntington's disease models.
- PGC-1α is a crucial mediator of meldonium's benefits, highlighting its potential as a therapeutic target in HD.
- Targeting PGC-1α offers a promising strategy for managing mitochondrial dysfunction and neurodegeneration in Huntington's disease.