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The involvement of cyclosporin A binding proteins in regulating and uncoupling mitochondrial energy transduction
M Crompton1, O McGuinness, W Nazareth
1Department of Biochemistry and Molecular Biology, University College London, UK.
Abstract:
The uncoupling of mitochondrial energy transduction by excess Ca2+ may be a factor in the pathogenesis of tissue injury brought about by energy deprivation, for example, in ischaemia. In isolated mitochondria the lesion appears as a large, 20 A, pore in the inner membrane. The pore is blocked potently by the immunosuppressant cyclosporin A. Cyclosporin A also markedly retards collapse of the mitochondrial inner membrane potential in energy-deprived (respiration-inhibited) cardiomyocytes as judged by changes in rhodamine 123 fluorescence, and prolongs cell viability. A potential mitochondrial target for cyclosporin A is the matrix protein cyclophilin. Purified cyclophilin activates the respiratory chain of submitochondrial particles. This might reflect not only a physiological function of this protein, but also a component involved in the generation of the 20 A pore under pathological conditions.
Insights
Excess calcium (Ca2+) can cause mitochondrial pores, leading to cell injury during ischemia. Cyclosporin A blocks these pores, preserving mitochondrial function and cell survival in energy-deprived heart cells.
Area of Science:
- Mitochondrial physiology and bioenergetics
- Cardiovascular pathology and ischemia-reperfusion injury
- Pharmacology of immunosuppressants
Background:
- Mitochondrial energy transduction uncoupling by excess calcium (Ca2+) is implicated in tissue injury during energy deprivation, such as ischemia.
- This pathological process involves the formation of a large pore (20 Å) in the mitochondrial inner membrane.
- The immunosuppressant cyclosporin A demonstrates potent inhibition of this mitochondrial pore.
Purpose of the Study:
- To investigate the role of mitochondrial pores in ischemia-induced tissue injury.
- To evaluate the protective effects of cyclosporin A on mitochondrial function and cell viability under energy deprivation.
- To identify potential molecular targets of cyclosporin A within the mitochondria.
Main Methods:
- Isolation and study of mitochondria to characterize the Ca2+-induced pore.
- Assessment of mitochondrial inner membrane potential collapse in cardiomyocytes using rhodamine 123 fluorescence.
- Investigation of the interaction between cyclosporin A, cyclophilin, and mitochondrial function.
Main Results:
- Excess Ca2+ induces a 20 Å pore in the mitochondrial inner membrane, disrupting energy transduction.
- Cyclosporin A effectively blocks this pore and significantly delays mitochondrial membrane potential collapse in energy-deprived cardiomyocytes.
- Cyclosporin A treatment prolongs the viability of energy-deprived cardiomyocytes.
- The mitochondrial matrix protein cyclophilin, a potential target for cyclosporin A, activates the respiratory chain.
Conclusions:
- Mitochondrial pore formation due to excess Ca2+ contributes to cell injury during ischemia.
- Cyclosporin A offers significant protection against ischemia-induced mitochondrial dysfunction and cell death by inhibiting these pores.
- Cyclophilin may play a role in both the physiological function of the respiratory chain and the pathological pore formation.