Proton selective substate of the mitochondrial permeability transition pore: regulation by the redox state of the electron transport chain.
The permeability transition pore of rat liver mitochondria can be closed by chelating free Ca2+, with respect to the passage of large molecules such as mannitol and sucrose. However, an apparent H+-conducting substate remains open under these conditions, as indicated by the persistence of maximal O2 consumption rates and by the failure to recover a membrane potential. Agents which favor a closed pore, such as cyclosporin A, ADP, Mg2+, or bovine serum albumin, do not close the H+-conducting substate, but it closes spontaneously when respiration becomes limited by the availability of O2. Closure provoked by an O2 limitation requires free Mg2+ in the sub-micromolar concentration range and becomes less efficient with increasing time spent in the presence of free Ca2+. The H+-conducting substate is apparently regulated by the redox status of the electron transport chain, with a reduced form favoring closure. A physical association (or equivalence) between the pore and one of the respiratory chain complexes is supported. These characteristics suggest that the transition is irreversible in vivo, if it involves a small fraction of total mitochondria, and would lead to their elimination and/or replacement by the cell. The implications of this proposal are considered, as they relate to a possible role for the transition in cellular apoptosis and the elimination of mitochondria containing mutated DNA.
Broekemeier
K M
KM
Department of Medical Biochemistry, The Ohio State University, Columbus 43210-1218, USA.
Klocek
C K
CK
Pfeiffer
D R
DR
D000693:Anaerobiosis; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000502:physiology; D004492:Edetic Acid / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism*; D008933:Mitochondrial Swelling / Q000187:drug effects; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010539:Permeability / Q000187:drug effects; D010710:Phosphates / Q000502:physiology; D011092:Polyethylene Glycols / Q000494:pharmacology; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley
D010710:Phosphates; D011522:Protons; D011092:Polyethylene Glycols; D004533:Egtazic Acid; D004492:Edetic Acid; D002118:Calcium