Journal of Bioenergetics and Biomembranes, Vol. 31, No. 4, 1999 Progress on the Mitochondrial Permeability Transition Pore: Regulation by Complex I and Ubiquinone Analogs Eric Fontaine 1 and Paolo Bernardi 2,3 This review summarizes recent progress on the regulation of the mitochondrial permeability transition pore, an inner membrane channel that may play a role in cell death. We briefly cover its key control points as emerged over the last few years from studies on isolated mitochondria; and describe in some detail our recent results indicating that the pore is modulated by the respiratory chain complex I and can be specifically blocked by selected ubiquinone analogs. We discuss the potential relevance of these findings for the structural definition of the permeability transition pore and illustrate the pharmacological perspectives they offer in diseases where mitochondrial dysfunction is suspected to play a key role. KEY WORDS: Mitochondrial channels; respiratory chain; complex I; ubiquinone; cell death; disease; aging. INTRODUCTION et al., 1994; Gunter and Gunter, 1994; Zoratti and Szabo, 1995 for reviews). As a result of Ca 2+ accumulation, or simply as In the 1970s, Pfeiffer and co-workers proposed the a consequence of in vitro “aging,” mitochondria can “membrane” theory of the permeability transition. The undergo a generalized increase of permeability of the defect was traced to the membrane itself, which would inner membrane, which has been termed “permeability undergo major changes of permeability as a result of the transition” (Haworth and Hunter, 1979; Hunter and accumulation of acyllysophospholipids following acti- Haworth, 1979a, b). The permeability pathway has an vation of Ca 2+ -dependent phospholipase A 2 (Pfeiffer et exclusion limit of approximately 1500 Da, which al., 1979; Beatrice et al., 1980). This theory accounted means that PTP opening leads to collapse of the proton- for the effects of a variety of inducers and inhibitors, motive force, disruption of ionic homeostasis, loss of and could also readily explain the lack of selectivity of pyridine nucleotides, and hydrolysis of ATP by the the permeability pathway. An alternative theory, which F 1 F 0 -ATPase. The permeability transition has long had already been proposed in the early 1970s (Massari been considered as an unspecific form of membrane and Azzone, 1972), considered the permeability transi- damage, possibly due to breakdown of the phospho- tion as linked to reversible opening of a pore. The pore lipid bilayer (see Gunter and Pfeiffer, 1990; Bernardi theory was fully developed in the late 1970s (Haworth and Hunter, 1979; Hunter and Haworth, 1979a,b), but it did not gain much consensus. Only with the demonstra- 1 Laboratoire de Bioe ´nerge ´tique Fondamentale et Applique ´e, Uni- tion that the permeability transition could be inhibited versite ´ J. Fourier, F-38041 Grenoble, France. by nanomolar concentrations of cyclosporin A (CsA) 2 Consiglio Nazionale delle Ricerche Unit for the Study of Biomem- branes and the Laboratory of Biophysics and Membrane Biology, did the pore theory become established (Fournier et al., Department of Biomedical Sciences, University of Padova Medi- 1987; Crompton et al., 1988; Broekemeier et al., 1989). cal School, I-35121 Padova, Italy. The electrophysiological demonstration that the mito- 3 Author to whom all correspondence should be sent: Dipartimento chondrial megachannel, a high-conductance inner di Scienze Biomediche Sperimentali, Viale Giuseppe Colombo 3, I-35121 Padova, Italy. membrane channel (Kinnally et al., 1989; Petronilli et 335 0145-479X/99/0800-0335$16.00/0  1999 Plenum Publishing Corporation