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Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess

Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess

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Inhibition of complex I regulates the mitochondrial permeability transition through a phosphate-sensitive inhibitory

Bo Li¹, Christiane Chauvin, Damien De Paulis

¹University Claude Bernard Lyon 1, Lyon, France.

Biochimica Et Biophysica Acta

|June 5, 2012

Abstract:

Inhibition of the mitochondrial permeability transition pore (PTP) has proved to be an effective strategy for preventing oxidative stress-induced cell death, and the pore represents a viable cellular target for drugs. Here, we report that inhibition of complex I by rotenone is more effective at PTP inhibition than cyclosporin A in tissues that express low levels of the cyclosporin A mitochondrial target, cyclophilin D; and, conversely, that tissues in which rotenone does not affect the PTP are characterized by high levels of expression of cyclophilin D and sensitivity to cyclosporin A. Consistent with a regulatory role of complex I in the PTP-inhibiting effects of rotenone, the concentrations of the latter required for PTP inhibition precisely match those required to inhibit respiration; and a similar effect is seen with the antidiabetic drug metformin, which partially inhibits complex I. Remarkably (i) genetic ablation of cyclophilin D or its displacement with cyclosporin A restored PTP inhibition by rotenone in tissues that are otherwise resistant to its effects; and (ii) rotenone did not inhibit the PTP unless phosphate was present, in striking analogy with the phosphate requirement for the inhibitory effects of cyclosporin A [Basso et al. (2008) J. Biol. Chem. 283, 26307-26311]. These results indicate that inhibition of complex I by rotenone or metformin and displacement of cyclophilin D by cyclosporin A affect the PTP through a common mechanism; and that cells can modulate their PTP response to complex I inhibition by modifying the expression of cyclophilin D, a finding that has major implications for pore modulation in vivo.

Insights

Inhibiting mitochondrial complex I with rotenone or metformin is a potent strategy for blocking the mitochondrial permeability transition pore (PTP). Cellular levels of cyclophilin D regulate PTP response to complex I inhibition.

Area of Science:

Mitochondrial Biology
Cell Death Mechanisms
Pharmacology

Background:

The mitochondrial permeability transition pore (PTP) is a key target for preventing cell death induced by oxidative stress.
Cyclosporin A inhibits the PTP by targeting cyclophilin D, a mitochondrial protein.
Complex I of the electron transport chain is involved in cellular respiration and potentially PTP regulation.

Purpose of the Study:

To investigate the comparative efficacy of rotenone and cyclosporin A in inhibiting the PTP.
To elucidate the role of cyclophilin D in modulating the PTP response to complex I inhibition.
To explore the mechanism by which complex I inhibitors affect PTP opening.

Main Methods:

Comparative analysis of PTP inhibition by rotenone and cyclosporin A in tissues with varying cyclophilin D levels.
Assessment of rotenone's effect on PTP in conjunction with genetic ablation or pharmacological displacement of cyclophilin D.
Investigation of the requirement for phosphate in rotenone-induced PTP inhibition.

Main Results:

Rotenone was more effective than cyclosporin A at inhibiting the PTP in tissues with low cyclophilin D expression.
Conversely, tissues with high cyclophilin D expression were sensitive to cyclosporin A but resistant to rotenone's PTP inhibitory effects.
Genetic or pharmacological removal of cyclophilin D restored rotenone's PTP inhibitory capacity, and rotenone's PTP inhibition required phosphate, similar to cyclosporin A.

Conclusions:

Inhibition of mitochondrial complex I by rotenone or metformin and cyclophilin D displacement by cyclosporin A share a common PTP inhibition mechanism.
Cellular cyclophilin D levels dictate the PTP response to complex I inhibition, offering a mechanism for in vivo PTP modulation.
This study highlights a novel therapeutic strategy targeting mitochondrial complex I for PTP-related pathologies.

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