Document Actions
Alterations in mitochondrial function in ... of hypertrophic cardiomyopathy
Alterations in mitochondrial function in a mouse model of hypertrophic cardiomyopathy.
24
Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease characterized by varying degrees of ventricular hypertrophy and myofibrillar disarray. Mutations in cardiac contractile proteins cause HCM. However, there is an unexplained wide variability in the clinical phenotype, and it is likely that there are multiple contributing factors. Because mitochondrial dysfunction has been described in heart disease, we tested the hypothesis that mitochondrial dysfunction contributes to the varying HCM phenotypes. Mitochondrial function was assessed in two transgenic models of HCM: mice with a mutant myosin heavy chain gene (MyHC) or with a mutant cardiac troponin T (R92Q) gene. Despite mitochondrial ultrastructural abnormalities in both models, the rate of state 3 respiration was significantly decreased only in the mutant MyHC mice by approximately 23%. Notably, this decrease in state 3 respiration preceded hemodynamic dysfunction. The maximum activity of alpha-ketogutarate dehydrogenase as assayed in isolated disrupted mitochondria was decreased by 28% compared with isolated control mitochondria. In addition, complexes I and IV were decreased in mutant MyHC transgenic mice. Inhibition of beta-adrenergic receptor kinase, which is elevated in mutant MyHC mouse hearts, can prevent mitochondrial respiratory impairment in mutant MyHC mice. Thus our results suggest that mitochondria may contribute to the hemodynamic dysfunction seen in some forms of HCM and offer a plausible mechanism responsible for some of the heterogeneity of the disease phenotypes.
Lucas DT, Aryal P, Szweda LI, Koch WJ, Leinwand LA
American journal of physiology. Heart and circulatory physiology
2003-02-01 00:00
284
2
H575-83
Animals,Cardiomyopathy, Hypertrophic,Electron Transport Complex I,Electron Transport Complex IV,Hemodynamic Processes,Hybridization, Genetic,Ketoglutarate Dehydrogenase Complex,Mice,Mice, Mutant Strains,Mice, Transgenic,Mitochondria, Heart,Myosin Heavy Chains,NADH, NADPH Oxidoreductases,Oxygen Consumption,Troponin T,Myosin Heavy Chains,Troponin T,Ketoglutarate Dehydrogenase Complex,NADH, NADPH Oxidoreductases,Electron Transport Complex I,Electron Transport Complex IV
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder 80309, USA
Am. J. Physiol. Heart Circ. Physiol.
NHLBI 1-F32-HL-10423-01, NHLBI HL-56510
0363-6135
10.1152/ajpheart.00619.2002
00619.2002
677
True
12414446
