Trends in Cell Biology
ReviewMitochondrial Permeability Transition: New Findings and Persisting Uncertainties
Section snippets
MPT: An Etiological Determinant of Disease
Although cells subjected to harsh microenvironmental conditions (e.g., extreme temperatures, intense shear forces, high pressures) die in a virtually instantaneous and incontrollable manner that reflects the physical disassembly of the plasma membrane, this is a relatively rare event [1]. More often, cells experiencing perturbations of the intracellular or extracellular microenvironment first activate programs that aim at restoring homeostasis, and only die when such adaptive responses fail 2, 3
Molecular Mechanisms of MPT
MPT was first observed in the mid-1950s, and since then an intense wave of investigation has attempted to clarify the underlying molecular mechanisms. Such an experimental effort culminated in the generation of a model proposing that MPT is mediated by the irreversible opening of a multiprotein pore assembled at the juxtaposition of the inner and outer mitochondrial membranes, the PTPC 11, 16. Initially, the activity of the PTPC was characterized via in vitro pharmacological studies, resulting
Solved and Persisting Controversies on MPT
Perhaps the first controversy about MPT was whether the PTPC would mediate lethal effects upon opening or closing [55], but this is one of the few aspects of the PTPC biology that appears to be solved. Findings from several independent laboratories indicate that MPT follows the sustained transition of the PTPC from a state of low conductance to a state of high conductance. In this situation, small solutes that are normally excluded from the mitochondrial matrix gain free access to it, and enter
Concluding Remarks
Several causes can be invoked to explain the persistence of controversies despite several decades of investigation on MPT. First, a significant amount of research has been carried out in rather artificial models, including reconstituted proteoliposomes and planar lipid bilayers. Both these systems are valuable tools to study transmembrane protein channels, but suffer from various limitations, including the confounding effects of protein concentration (often supraphysiological) and test buffers
Acknowledgments
V.I. received a fellowship from Fondation pour la Recherche Médicale (FRM). G.K. is supported by the Ligue Contre le Cancer (Equipe Labellisée); Agence National de la Recherche (ANR) – Projets Blancs; ANR within the framework of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association Pour la Recherche sur le Cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; FRM; the European Commission (ArtForce); the
Glossary
- Calcineurin
- a heterodimeric Ca2+- and calmodulin-dependent serine/threonine protein phosphatase that is crucial for the proliferation and activation of T lymphocytes.
- Cyclosporin A (CsA)
- cyclic non-ribosomal peptide of fungal origin currently approved by regulatory agencies as an immunosuppressant. CsA is also a potent inhibitor of MPT, owing to its ability to target CYPD.
- Floxing
- genetic procedure in which a loxP site is placed on both sides of a specific region of nuclear DNA. This allows for
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