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Cardiac mitochondria in heart failure: decrease in respirasomes and oxidative phosphorylation.

Rosca MG, Vazquez EJ, Kerner J, Parland W, Chandler MP, Stanley W, Sabbah HN, Hoppel CL - Cardiovasc. Res. (2008)

Bottom Line: We found a dramatic decrease in ADP-stimulated respiration that was not relieved by an uncoupler.The amount of the supercomplex consisting of complex I/complex III dimer/complex IV, the major form of respirasome considered essential for oxidative phosphorylation, was decreased.We propose that the mitochondrial defect lies in the supermolecular assembly rather than in the individual components of the ETC.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland 44106-4981, OH, USA.

ABSTRACT

Aims: Mitochondrial dysfunction is a major factor in heart failure (HF). A pronounced variability of mitochondrial electron transport chain (ETC) defects is reported to occur in severe acquired cardiomyopathies without a consistent trend for depressed activity or expression. The aim of this study was to define the defect in the integrative function of cardiac mitochondria in coronary microembolization-induced HF.

Methods and results: Studies were performed in the canine coronary microembolization-induced HF model of moderate severity. Oxidative phosphorylation was assessed as the integrative function of mitochondria, using a comprehensive variety of substrates in order to investigate mitochondrial membrane transport, dehydrogenase activity and electron-transport coupled to ATP synthesis. The supramolecular organization of the mitochondrial ETC also was investigated by native gel electrophoresis. We found a dramatic decrease in ADP-stimulated respiration that was not relieved by an uncoupler. Moreover, the ADP/O ratio was normal, indicating no defect in the phosphorylation apparatus. The data point to a defect in oxidative phosphorylation within the ETC. However, the individual activities of ETC complexes were normal. The amount of the supercomplex consisting of complex I/complex III dimer/complex IV, the major form of respirasome considered essential for oxidative phosphorylation, was decreased.

Conclusions: We propose that the mitochondrial defect lies in the supermolecular assembly rather than in the individual components of the ETC.

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Related in: MedlinePlus

The activity of electron transport chain enzymes in isolated heart subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). The enzyme activity was measured in detergent-solubilized, freshly isolated SSM and IFM from control (n = 5) and heart failure (n = 5) dogs, and expressed as nmol/min/mg mitochondrial protein or as the first-order rate constant (k = 1/min/mg mitochondrial protein) for complex IV. NCR, rotenone sensitive NADH-Cytochrome c Reductase; C I, complex I; NFR, NADH-Ferricyanide Reductase; SCR, antimycin A-sensitive Succinate-Cytochrome c Reductase. C II, TTFA-sensitive complex II; C II+Q, TTFA-sensitive Complex II with exogenous coenzyme Q analogue; C III, complex III; C IV, complex IV. Mean ± SEM.
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CVN184F3: The activity of electron transport chain enzymes in isolated heart subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). The enzyme activity was measured in detergent-solubilized, freshly isolated SSM and IFM from control (n = 5) and heart failure (n = 5) dogs, and expressed as nmol/min/mg mitochondrial protein or as the first-order rate constant (k = 1/min/mg mitochondrial protein) for complex IV. NCR, rotenone sensitive NADH-Cytochrome c Reductase; C I, complex I; NFR, NADH-Ferricyanide Reductase; SCR, antimycin A-sensitive Succinate-Cytochrome c Reductase. C II, TTFA-sensitive complex II; C II+Q, TTFA-sensitive Complex II with exogenous coenzyme Q analogue; C III, complex III; C IV, complex IV. Mean ± SEM.

Mentions: The individual activities of the mitochondrial ETC enzymes were not affected (Figure 3). In addition, COX activity, measured under isosmotic conditions to assess outer membrane leakage, was 3.2 ± 1 and 2.5 ± 0.5% of the total activity in control SSM and IFM, respectively, and was not modified in HF. These data show that the outer membrane is essentially intact and is preserved in HF in both heart mitochondrial populations.


Cardiac mitochondria in heart failure: decrease in respirasomes and oxidative phosphorylation.

Rosca MG, Vazquez EJ, Kerner J, Parland W, Chandler MP, Stanley W, Sabbah HN, Hoppel CL - Cardiovasc. Res. (2008)

The activity of electron transport chain enzymes in isolated heart subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). The enzyme activity was measured in detergent-solubilized, freshly isolated SSM and IFM from control (n = 5) and heart failure (n = 5) dogs, and expressed as nmol/min/mg mitochondrial protein or as the first-order rate constant (k = 1/min/mg mitochondrial protein) for complex IV. NCR, rotenone sensitive NADH-Cytochrome c Reductase; C I, complex I; NFR, NADH-Ferricyanide Reductase; SCR, antimycin A-sensitive Succinate-Cytochrome c Reductase. C II, TTFA-sensitive complex II; C II+Q, TTFA-sensitive Complex II with exogenous coenzyme Q analogue; C III, complex III; C IV, complex IV. Mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2533423&req=5

CVN184F3: The activity of electron transport chain enzymes in isolated heart subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). The enzyme activity was measured in detergent-solubilized, freshly isolated SSM and IFM from control (n = 5) and heart failure (n = 5) dogs, and expressed as nmol/min/mg mitochondrial protein or as the first-order rate constant (k = 1/min/mg mitochondrial protein) for complex IV. NCR, rotenone sensitive NADH-Cytochrome c Reductase; C I, complex I; NFR, NADH-Ferricyanide Reductase; SCR, antimycin A-sensitive Succinate-Cytochrome c Reductase. C II, TTFA-sensitive complex II; C II+Q, TTFA-sensitive Complex II with exogenous coenzyme Q analogue; C III, complex III; C IV, complex IV. Mean ± SEM.
Mentions: The individual activities of the mitochondrial ETC enzymes were not affected (Figure 3). In addition, COX activity, measured under isosmotic conditions to assess outer membrane leakage, was 3.2 ± 1 and 2.5 ± 0.5% of the total activity in control SSM and IFM, respectively, and was not modified in HF. These data show that the outer membrane is essentially intact and is preserved in HF in both heart mitochondrial populations.

Bottom Line: We found a dramatic decrease in ADP-stimulated respiration that was not relieved by an uncoupler.The amount of the supercomplex consisting of complex I/complex III dimer/complex IV, the major form of respirasome considered essential for oxidative phosphorylation, was decreased.We propose that the mitochondrial defect lies in the supermolecular assembly rather than in the individual components of the ETC.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland 44106-4981, OH, USA.

ABSTRACT

Aims: Mitochondrial dysfunction is a major factor in heart failure (HF). A pronounced variability of mitochondrial electron transport chain (ETC) defects is reported to occur in severe acquired cardiomyopathies without a consistent trend for depressed activity or expression. The aim of this study was to define the defect in the integrative function of cardiac mitochondria in coronary microembolization-induced HF.

Methods and results: Studies were performed in the canine coronary microembolization-induced HF model of moderate severity. Oxidative phosphorylation was assessed as the integrative function of mitochondria, using a comprehensive variety of substrates in order to investigate mitochondrial membrane transport, dehydrogenase activity and electron-transport coupled to ATP synthesis. The supramolecular organization of the mitochondrial ETC also was investigated by native gel electrophoresis. We found a dramatic decrease in ADP-stimulated respiration that was not relieved by an uncoupler. Moreover, the ADP/O ratio was normal, indicating no defect in the phosphorylation apparatus. The data point to a defect in oxidative phosphorylation within the ETC. However, the individual activities of ETC complexes were normal. The amount of the supercomplex consisting of complex I/complex III dimer/complex IV, the major form of respirasome considered essential for oxidative phosphorylation, was decreased.

Conclusions: We propose that the mitochondrial defect lies in the supermolecular assembly rather than in the individual components of the ETC.

Show MeSH
Related in: MedlinePlus