Dysfunction of the ADP/ATP carrier as a causative factor for the disturbance of the myocardial energy metabolism in dilated cardiomyopathy
The adenine nucleotide translocator (ADP/ATP carrier) plays a key role in nucleotide transport across the mitochondrial membrane. The quantity and function of this transport protein were investigated in myocardium from hearts with endstage failing dilated and ischemic cardiomyopathy, and were compared to measurements in nonfailing myocardium. In addition, lactate dehydrogenase (LDH) isoenzymes were determined. The concentration of the ADP/ATP carrier was significantly increased by 48% in myocardium from dilated cardiomyopathic hearts compared to control myocardium. The concentration of the carrier in explaitted hearts with ischemic cardiomyopathy did not differ from values in the normal human hearts. Analysis of carrier function revealed similar nucleotide exchange rates in control hearts and hearts with ischemic cardiomyopathy, whereas carrier function was reduced in most hearts with dilated cardiomyopathy. Compared to control hearts, in hearts with dilated cardiomyopathy and decreased nucleotide exchange rate, the carrier content was significantly higher, whereas the carrier content was only slightly increased compared to control in cardiomyopathic hearts with unchanged transport activity. Compared to control hearts, in dilated cardiomyopathy there was a significant increase in LDH5 and a decrease in LDH1 isoforms, indicating more anaerobic metabolism in failing dilated cardiomyopathic hearts.
KeywordsADP/ATP carrier mitochondria lactate dehydrogenase dilated cardiomyopathy nucleotide transport
Unable to display preview. Download preview PDF.
- 3.Bishop SP, Altschuld RA (1971) Evidence for increased glycolytic metabolism in cardiac hypertrophy and congestive heart failure. In: Alpert NA (ed). Cardiac Hypertrophy. New York: Academic Press pp 567–585Google Scholar
- 4.Everse J, Kaplan NO (1975) Mechanisms of action and biological functions of various dehydrogenase isoenzymes. In: Markert CL (ed). Isoenzymes. II. Physiological functions. New York: Academic pp 29–43Google Scholar
- 9.Klingenberg M, Heidt HW (1982) The ADP/ATP translocation in mitochondria and its role in intracellular compartmentation. In: Sies H (ed). Metabolic Compartmentation. London: Academic Press pp 101–122Google Scholar
- 10.Klingenberg M (1985) The ADP/ATP carrier in mitochondrial membranes. In: Martonosi AN (ed). The Enzymes of Biological Membranes. Vol. 4. New York: Plenum Publishing pp 511–553Google Scholar
- 13.Nadal-Ginard B, Markert CL (1975) Use of affinity chromatography for purification of lactate dehydrogenase and for assessing the homology and function of the A and B subunits. In:. Markert CL (ed). Isoenzymes. II. Physiological Functions. New York: Academic pp 45–67Google Scholar
- 14.Neckelmann N, Li K, Wade RP, Shuster R, Wallace DC (1987) cDNA sequence of a human skeletal muscle ADP/ATP translocator: lack of a leader peptide, divergence from a fibroblast translocator cDNA, and coevolution with mitochondrial DNA genes. Proc Natl Acad Sci 84: 7580–7584Google Scholar
- 15.Palmieri F, Klingenberg M (1979) Direct methods for measuring metabolite transport and distribution in mitochondria. In: Sydney F, Lester P (eds). Methods in Enzymology. Vol. 56. New York: Academic Press pp 279–301Google Scholar
- 21.Schultheiss HP (1987) The mitochondrium as antigen in inflammatory heart disease. Eur Heart J 8: 203–210Google Scholar
- 23.Schultheiss HP (1991) Disturbance of the myocardial energy metabolism in dilated cardiomyoapthy due to autoimmunological mechanisms. Circulation (in press)Google Scholar
- 26.Smith AD (1967) Preparation, properties and conditions for assay of mitochondria: slaughterhouse material, small scale. In: Sydney F, Lester P (eds). Methods in Enzymology. Vol. 10. New York: Academic Press pp 81–86Google Scholar
- 31.Weiss MB, Ellis K, Sciacca RR, Johnson LL, Schmidt DH, Cannon PJ (1976) Myocardial blood flow in congestive and hypertrophic cardiomyopathy. Relationship to peak wall stress and mean velocity of circumferential fiber shortening. Circulation 54: 884–494Google Scholar