Myocardial overexpression of Mecr, a gene of mitochondrial FAS II leads to cardiac dysfunction in mouse

• Published in: PloS one Vol. 4; no. 5; p. e5589
• Main Authors: Chen, Zhijun, Leskinen, Hanna, Liimatta, Erkki, Sormunen, Raija T, Miinalainen, Ilkka J, Hassinen, Ilmo E, Hiltunen, J Kalervo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.05.2009; Public Library of Science (PLoS)
• Subjects: Abnormalities; Animals; Apoptosis; Biochemistry; Biophysics; Blotting, Northern; Blotting, Southern; Cardiomyopathy; Cardiovascular Disorders; Echocardiography; Electron microscopy; Enzymes; Exercise; Exercise Test; fas Receptor - genetics; Fatigue tests; Fatty acids; Fitness training programs; Gene Expression; Genes; Genetic engineering; Heart; Heart diseases; Heart Diseases - genetics; Heart Diseases - physiopathology; Heart failure; Heart function; In Situ Nick-End Labeling; In vivo methods and tests; Kinases; Male; Mammals; Metallothionein; Mice; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - physiology; Molecular biology; Myocardium - metabolism; NADP; Oxidoreductases Acting on CH-CH Group Donors - genetics; Oxidoreductases Acting on CH-CH Group Donors - metabolism; Oxygen Consumption - genetics; Oxygen Consumption - physiology; Perfusion; Physiological aspects; Proteins; Reductase; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Synthesis; Thioesters; Transgenic animals; Transgenic mice; Ventricle
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0005589

It has been recently recognized that mammalian mitochondria contain most, if not all, of the components of fatty acid synthesis type II (FAS II). Among the components identified is 2-enoyl thioester reductase/mitochondrial enoyl-CoA reductase (Etr1/Mecr), which catalyzes the NADPH-dependent reduction of trans-2-enoyl thioesters, generating saturated acyl-groups. Although the FAS type II pathway is highly conserved, its physiological role in fatty acid synthesis, which apparently occurs simultaneously with breakdown of fatty acids in the same subcellular compartment in mammals, has remained an enigma. To study the in vivo function of the mitochondrial FAS in mammals, with special reference to Mecr, we generated mice overexpressing Mecr under control of the mouse metallothionein-1 promoter. These Mecr transgenic mice developed cardiac abnormalities as demonstrated by echocardiography in vivo, heart perfusion ex vivo, and electron microscopy in situ. Moreover, the Mecr transgenic mice showed decreased performance in endurance exercise testing. Our results showed a ventricular dilatation behind impaired heart function upon Mecr overexpression, concurrent with appearance of dysmorphic mitochondria. Furthermore, the data suggested that inappropriate expression of genes of FAS II can result in the development of hereditary cardiomyopathy.