Trimetazidine prevents palmitate-induced mitochondrial fission and dysfunction in cultured cardiomyocytes

Jovan Kuzmicic, Valentina Parra, Hugo E. Verdejo, Camila López-Crisosto, Mario Chiong, Lorena García, Michael Dennis Jensen, David A. Bernlohr, Pablo F. Castro, Sergio Lavandero

Research output: Contribution to journalArticle

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Abstract

Metabolic and cardiovascular disease patients have increased plasma levels of lipids and, specifically, of palmitate, which can be toxic for several tissues. Trimetazidine (TMZ), a partial inhibitor of lipid oxidation, has been proposed as a metabolic modulator for several cardiovascular pathologies. However, its mechanism of action is controversial. Given the fact that TMZ is able to alter mitochondrial metabolism, we evaluated the protective role of TMZ on mitochondrial morphology and function in an in vitro model of lipotoxicity induced by palmitate. We treated cultured rat cardiomyocytes with BSA-conjugated palmitate (25 nM free), TMZ (0.1-100 μM), or a combination of both. We evaluated mitochondrial morphology and lipid accumulation by confocal fluorescence microscopy, parameters of mitochondrial metabolism (mitochondrial membrane potential, oxygen consumption rate [OCR], and ATP levels), and ceramide production by mass spectrometry and indirect immunofluorescence. Palmitate promoted mitochondrial fission evidenced by a decrease in mitochondrial volume (50%) and an increase in the number of mitochondria per cell (80%), whereas TMZ increased mitochondrial volume (39%), and decreased mitochondrial number (56%), suggesting mitochondrial fusion. Palmitate also decreased mitochondrial metabolism (ATP levels and OCR), while TMZ potentiated all the metabolic parameters assessed. Moreover, pretreatment with TMZ protected the cardiomyocytes from palmitate-induced mitochondrial fission and dysfunction. TMZ also increased lipid accumulation in cardiomyocytes, and prevented palmitate-induced ceramide production. Our data show that TMZ protects cardiomyocytes by changing intracellular lipid management. Thus, the beneficial effects of TMZ on patients with different cardiovascular pathologies can be related to modulation of the mitochondrial morphology and function.

Original languageEnglish (US)
Pages (from-to)323-336
Number of pages14
JournalBiochemical Pharmacology
Volume91
Issue number3
DOIs
StatePublished - Aug 1 2014

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Trimetazidine
Mitochondrial Dynamics
Palmitates
Cardiac Myocytes
Lipids
Metabolism
Mitochondrial Size
Ceramides
Pathology
Oxygen Consumption
Adenosine Triphosphate
Oxygen
Mitochondria
Confocal microscopy
Mitochondrial Membrane Potential
Poisons
Fluorescence microscopy
Metabolic Diseases
Corrosion inhibitors
Indirect Fluorescent Antibody Technique

Keywords

  • Cardiomyocyte
  • Metabolism
  • Mitochondrial dynamics
  • Palmitate
  • Trimetazidine

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Kuzmicic, J., Parra, V., Verdejo, H. E., López-Crisosto, C., Chiong, M., García, L., ... Lavandero, S. (2014). Trimetazidine prevents palmitate-induced mitochondrial fission and dysfunction in cultured cardiomyocytes. Biochemical Pharmacology, 91(3), 323-336. https://doi.org/10.1016/j.bcp.2014.07.022

Trimetazidine prevents palmitate-induced mitochondrial fission and dysfunction in cultured cardiomyocytes. / Kuzmicic, Jovan; Parra, Valentina; Verdejo, Hugo E.; López-Crisosto, Camila; Chiong, Mario; García, Lorena; Jensen, Michael Dennis; Bernlohr, David A.; Castro, Pablo F.; Lavandero, Sergio.

In: Biochemical Pharmacology, Vol. 91, No. 3, 01.08.2014, p. 323-336.

Research output: Contribution to journalArticle

Kuzmicic, J, Parra, V, Verdejo, HE, López-Crisosto, C, Chiong, M, García, L, Jensen, MD, Bernlohr, DA, Castro, PF & Lavandero, S 2014, 'Trimetazidine prevents palmitate-induced mitochondrial fission and dysfunction in cultured cardiomyocytes', Biochemical Pharmacology, vol. 91, no. 3, pp. 323-336. https://doi.org/10.1016/j.bcp.2014.07.022
Kuzmicic, Jovan ; Parra, Valentina ; Verdejo, Hugo E. ; López-Crisosto, Camila ; Chiong, Mario ; García, Lorena ; Jensen, Michael Dennis ; Bernlohr, David A. ; Castro, Pablo F. ; Lavandero, Sergio. / Trimetazidine prevents palmitate-induced mitochondrial fission and dysfunction in cultured cardiomyocytes. In: Biochemical Pharmacology. 2014 ; Vol. 91, No. 3. pp. 323-336.
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AU - Chiong, Mario

AU - García, Lorena

AU - Jensen, Michael Dennis

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