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Role of mitochondrial calcium transport in failing heart
Insights
Mitochondrial calcium transport is impaired in failing hearts, with uptake reduced in various species and conditions. Factors like pH and energy levels significantly influence this crucial process in heart failure.
Area of Science:
- Cardiology
- Mitochondrial Physiology
- Biochemistry
Background:
- Mitochondrial calcium handling is vital for cardiac function.
- Dysfunctional calcium transport is implicated in heart failure.
Purpose of the Study:
- To investigate mitochondrial calcium uptake and binding in failing hearts.
- To identify factors affecting mitochondrial calcium transport during heart failure.
Main Methods:
- Comparative analysis of mitochondrial calcium uptake in control and failing hearts (dog, rabbit, hamster).
- Assessment of calcium transport inhibitors' effects on isolated rat hearts.
- Evaluation of mitochondrial calcium uptake under various ionic and metabolic conditions (Na+-free, K+-free, Ca++-free, substrate-free media, altered pH, ATP:ADP, ATP:AMP, K+:Na+ ratios).
Main Results:
- Mitochondrial calcium uptake, but not binding, was reduced in failing human, dog, rabbit, and hamster hearts.
- Genetically myopathic hamsters showed decreased mitochondrial calcium binding and uptake at all stages of heart failure.
- Inhibitors and altered ionic/metabolic conditions (low pH, low ATP:ADP, low K+:Na+) reduced mitochondrial calcium uptake, with some changes being secondary to contractility loss.
Conclusions:
- Mitochondrial calcium transport is significantly altered in heart failure, varying with the type and severity.
- Factors including pH, energy status (ATP:ADP, ATP:AMP ratios), and ion gradients (K+:Na+) are critical regulators of mitochondrial calcium uptake.
- Damage to mitochondrial structure and these metabolic factors likely contribute to impaired mitochondrial calcium transport in failing hearts.
Abstract:
Mitochondrial calcium uptake, but not binding, like microsomal calcium uptake in failing human hearts, was less than the control values for dog, rabbit, and hamster hearts. Decrease in mitochondrial calcium binding and uptake was observed in genetically myopathic hamsters (BIO 14.6) at early, moderate, and late stages of congestive heart failure. Inhibitors of mitochondrial calcium transport, Dicumarol, dinitrophenol, and sodium azide, were found to produce a rapid fall in contractility of the isolated rat heart. Inability of rat hearts to generate contractile force on perfusion with Na+- or K+-free medium was associated with an increase in mitochondrial calcium uptake. A dramatic increase in mitochondrial calcium uptake was observed on perfusing rat hearts with control medium after CA++-free medium. No change in mitochondrial calcium uptake was noted in acute ischemic dog myocardium or hypoxic rat heart in which contractile force was severely depressed. Both mitochondrial calcium transport and contractility were decreased on perfusing rat hearts with substrate-free medium; however, the change in calcium uptake was secondary to the fall in contractile force. Decrease in pH, ATP:ADP ratio, ATP6AMP ratio, and K+:Na+ ratio were found to reduce the dog heart mitochondrial calcium uptake. It is likely that various factors such as pH, ATP:ADP ration, ATP:AMP ratio, and K+ :Na+ ration, in addition to damage in mitochondrial structure, play an important role in inhibiting mitochondrial calcium transport in failing hearts. The results also suggest that alterations in mitochondrial calcium transport are dependent upon the degree and type of heart failure.