MEMBRANES AND BIOENERGETICS
Regulation of the Permeability Transition Pore in Skeletal Muscle Mitochondria: MODULATION BY ELECTRON FLOW THROUGH THE RESPIRATORY CHAIN COMPLEX I*

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We have investigated the regulation of the permeability transition pore (PTP), a cyclosporin A-sensitive channel, in rat skeletal muscle mitochondria. As is the case with mitochondria isolated from a variety of sources, skeletal muscle mitochondria can undergo a permeability transition following Ca2+uptake in the presence of Pi. We find that the PTP opening is dramatically affected by the substrates used for energization, in that much lower Ca2+ loads are required when electrons are provided to complex I rather than to complex II or IV. This increased sensitivity of PTP opening does not depend on differences in membrane potential, matrix pH, Ca2+ uptake, oxidation-reduction status of pyridine nucleotides, or production of H2O2, but is directly related to the rate of electron flow through complex I. Indeed, and with complex I substrates only, pore opening can be observed when depolarization is induced with uncoupler (increased electron flow) but not with cyanide (decreased electron flow). Consistent with pore regulation by electron flow, we find that PTP opening is inhibited by ubiquinone 0 at concentrations that partially inhibit respiration and do not depolarize the inner membrane. These data allow identification of a novel site of regulation of the PTP, suggest that complex I may be part of the pore complex, and open new perspectives for its pharmacological modulation in living cells.

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This work was supported in part by Grants from the Consiglio Nazionale delle Ricerche, Dotazione Centro and Grant 96.03009.CTO4 (to P. B), the Ministero dell'Università e della Ricerca Scientifica e Tecnologica (Progetto “Bioenergetica e Trasporto di Membrana”), Telethon-Italy Grant 847 (to P. B.), and the EEC Fellowship ERBFMBICT961385 (to E. F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Permanent address: Laboratoire de Bioénergétique Fondamentale et Appliquée, Université J. Fourier, F-38041 Grenoble, France.

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On leave from the Institute of Biomedicine, University of Helsinki, Helsinki Fin00014, Finland.

To whom reprint requests should be addressed: Dipartimento di Scienze Biomediche Sperimentali, Viale Giuseppe Colombo 3, I-35121 Padova, Italy.