title: Trimetazidine prevents palmitate-induced mitochondrial fission and dysfunction in cultured cardiomyocytes.
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.
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile & Pontificia Universidad Católica de Chile, Santiago, Chile; Centro Estudios Moleculares de la Célula, Facultad Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Jovan
authors.initials: J
authors.lastname: Kuzmicic
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile & Pontificia Universidad Católica de Chile, Santiago, Chile; Centro Estudios Moleculares de la Célula, Facultad Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Parra
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile & Pontificia Universidad Católica de Chile, Santiago, Chile; División de Enfermedades Cardiovasculares, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Hugo E
authors.initials: HE
authors.lastname: Verdejo
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile & Pontificia Universidad Católica de Chile, Santiago, Chile; Centro Estudios Moleculares de la Célula, Facultad Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Camila
authors.initials: C
authors.lastname: López-Crisosto
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile & Pontificia Universidad Católica de Chile, Santiago, Chile; Centro Estudios Moleculares de la Célula, Facultad Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Mario
authors.initials: M
authors.lastname: Chiong
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile & Pontificia Universidad Católica de Chile, Santiago, Chile; Centro Estudios Moleculares de la Célula, Facultad Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Lorena
authors.initials: L
authors.lastname: García
authors.affiliation: Endocrine Research Unit, Mayo Clinic, Rochester, MN, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Jensen
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bernlohr
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile & Pontificia Universidad Católica de Chile, Santiago, Chile; División de Enfermedades Cardiovasculares, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile. Electronic address: pcastro@med.puc.cl.
authors.forename: Pablo F
authors.initials: PF
authors.lastname: Castro
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile & Pontificia Universidad Católica de Chile, Santiago, Chile; Centro Estudios Moleculares de la Célula, Facultad Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: slavander@uchile.cl.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D034281:Dynamins / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D019308:Palmitic Acid / Q000009:adverse effects; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013107:Sphingolipids / Q000378:metabolism; D014292:Trimetazidine / Q000494:pharmacology*
chemical_list: D020011:Protective Agents; D013107:Sphingolipids; D019308:Palmitic Acid; D000255:Adenosine Triphosphate; C519851:Dnm1l protein, rat; D034281:Dynamins; D014292:Trimetazidine; D010100:Oxygen
keywords: Cardiomyocyte; Metabolism; Mitochondrial dynamics; Palmitate; Sodium palmitate CID 2735111; Trimetazidine; Trimetazidine CID 21109