Myocardial overexpression of Mecr, a gene of mitochondrial FAS II leads to cardiac dysfunction in mouse.
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.
Department of Biochemistry, Biocenter Oulu, University of Oulu, Oulu, Finland.
Zhijun
Z
Chen
Hanna
H
Leskinen
Erkki
E
Liimatta
Raija T
RT
Sormunen
Ilkka J
IJ
Miinalainen
Ilmo E
IE
Hassinen
J Kalervo
JK
Hiltunen
D000818:Animals; D015152:Blotting, Northern; D015139:Blotting, Southern; D004452:Echocardiography; D005080:Exercise Test; D015870:Gene Expression; D006331:Heart Diseases / Q000235:genetics / Q000503:physiopathology*; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019014:fas Receptor / Q000235:genetics
C491899:Fas protein, mouse; D024101:Mitochondrial Proteins; D019014:fas Receptor; D044925:Oxidoreductases Acting on CH-CH Group Donors; C434934:trans-2-enoyl-CoA reductase (NADPH)