Effects of decreasing mitochondrial volume on the regulation of the permeability transition pore.
The permeability transition pore (PTP) is a Ca(2+)-sensitive mitochondrial inner membrane channel involved in several models of cell death. Because the matrix concentration of PTP regulatory factors depends on matrix volume, we have investigated the role of the mitochondrial volume in PTP regulation. By incubating rat liver mitochondria in media of different osmolarity, we found that the Ca(2+) threshold required for PTP opening dramatically increased when mitochondrial volume decreased relative to the standard condition. This shrinkage-induced PTP inhibition was not related to the observed changes in protonmotive force, or pyridine nucleotide redox state and persisted when mitochondria were depleted of adenine nucleotides. On the other hand, mitochondrial volume did not affect PTP regulation when mitochondria were depleted of Mg(2+). By studying the effects of Mg(2+), cyclosporin A (CsA) and ubiquinone 0 (Ub(0)) on PTP regulation, we found that mitochondrial shrinkage increased the efficacy of Mg(2+) and Ub(0) at PTP inhibition, whereas it decreased that of CsA. The ability of mitochondrial volume to alter the activity of several PTP regulators represents a hitherto unrecognized characteristic of the pore that might lead to a new approach for its pharmacological modulation.
Nogueira
Véronique
V
INSERM E-0221 Bioénergétique Fondamentale et Appliquée, Université J. Fourier-BP53, F-38041 Grenoble Cedex, France.
Devin
Anne
A
Walter
Ludivine
L
Rigoulet
Michel
M
Leverve
Xavier
X
Fontaine
Eric
E
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D007473:Ion Channels / Q000502:physiology*; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009994:Osmolar Concentration; D010101:Oxygen Consumption; D010539:Permeability; D051381:Rats
D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D000001:Calcimycin; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D008274:Magnesium