The Mitochondrial Permeability Transition Pore: Channel Formation by F-ATP Synthase, Integration in Signal Transduction, and Role in Pathophysiology.
The mitochondrial permeability transition (PT) is a permeability increase of the inner mitochondrial membrane mediated by a channel, the permeability transition pore (PTP). After a brief historical introduction, we cover the key regulatory features of the PTP and provide a critical assessment of putative protein components that have been tested by genetic analysis. The discovery that under conditions of oxidative stress the F-ATP synthases of mammals, yeast, and Drosophila can be turned into Ca(2+)-dependent channels, whose electrophysiological properties match those of the corresponding PTPs, opens new perspectives to the field. We discuss structural and functional features of F-ATP synthases that may provide clues to its transition from an energy-conserving into an energy-dissipating device as well as recent advances on signal transduction to the PTP and on its role in cellular pathophysiology.
Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche Neuroscience Institute, University of Padova, Padova, Italy; Vollum Institute, Oregon Health and Sciences University, Portland, Oregon; and Department of Food Science, University of Udine, Udine, Italy.
Paolo
P
Bernardi
Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche Neuroscience Institute, University of Padova, Padova, Italy; Vollum Institute, Oregon Health and Sciences University, Portland, Oregon; and Department of Food Science, University of Udine, Udine, Italy.
Andrea
A
Rasola
Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche Neuroscience Institute, University of Padova, Padova, Italy; Vollum Institute, Oregon Health and Sciences University, Portland, Oregon; and Department of Food Science, University of Udine, Udine, Italy.
Michael
M
Forte
Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche Neuroscience Institute, University of Padova, Padova, Italy; Vollum Institute, Oregon Health and Sciences University, Portland, Oregon; and Department of Food Science, University of Udine, Udine, Italy.
Giovanna
G
Lippe
D000818:Animals; D006801:Humans; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D025261:Mitochondrial Proton-Translocating ATPases