Trends in Cell Biology
Volume 26, Issue 9, September 2016, Pages 655-667
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Review
Mitochondrial Permeability Transition: New Findings and Persisting Uncertainties

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MPT-driven necrosis is profoundly involved in the etiology of several pathological conditions characterized by the unwarranted loss of post-mitotic cells.

Excepting the crucial involvement of CYPD, the molecular mechanisms that precipitate MPT remain largely obscure.

Recent data indicate that the metalloprotease SPG7, the c subunit of F1FO-ATPase, or F1FO-ATPase dimers may have a fundamental role in MPT.

Robust genetic evidence demonstrating that SPG7, the c subunit of F1FO-ATPase, or F1FO-ATPase dimers are crucially required for MPT, however, is lacking.

Several aspects of MPT remain matter of debate, mostly due to the high degree of functional redundancy that characterizes the underlying molecular machinery, and to the intimate connection between MPT and bioenergetic metabolism.

Several insults cause the inner mitochondrial membrane to abruptly lose osmotic homeostasis, hence initiating a regulated variant of cell death known as ‘mitochondrial permeability transition’ (MPT)-driven necrosis. MPT provides an etiological contribution to several human disorders characterized by the acute loss of post-mitotic cells, including cardiac and cerebral ischemia. Nevertheless, the precise molecular determinants of MPT remain elusive, which considerably hampers the development of clinically implementable cardio- or neuroprotective strategies targeting this process. We summarize recent findings shedding new light on the supramolecular entity that mediates MPT, the so-called ‘permeability transition pore complex’ (PTPC). Moreover, we discuss hitherto unresolved controversies on MPT and analyze the major obstacles that still preclude the complete understanding and therapeutic targeting of this process.

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

References (78)

  • A.V. Vaseva

    p53 opens the mitochondrial permeability transition pore to trigger necrosis

    Cell

    (2012)
  • S. Shanmughapriya

    SPG7 is an essential and conserved component of the mitochondrial permeability transition pore

    Mol. Cell

    (2015)
  • V. Giorgio

    Cyclophilin D modulates mitochondrial F0F1-ATP synthase by interacting with the lateral stalk of the complex

    J. Biol. Chem.

    (2009)
  • I. Masgras

    Induction of the permeability transition pore in cells depleted of mitochondrial DNA

    Biochim. Biophys. Acta

    (2012)
  • M.G. Vander Heiden

    Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane

    J. Biol. Chem.

    (2001)
  • J.R. Hom

    The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation

    Dev. Cell

    (2011)
  • A.J. Kowaltowski

    Mitochondrial permeability transition and oxidative stress

    FEBS Lett.

    (2001)
  • L. He et al.

    Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function?

    FEBS Lett.

    (2002)
  • Z. Hao

    Specific ablation of the apoptotic functions of cytochrome c reveals a differential requirement for cytochrome c and Apaf-1 in apoptosis

    Cell

    (2005)
  • L. Galluzzi

    Caspases connect cell-death signaling to organismal homeostasis

    Immunity

    (2016)
  • L. Galluzzi

    Molecular mechanisms of regulated necrosis

    Semin. Cell Dev. Biol.

    (2014)
  • L. Galluzzi

    Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

    Cell Death Differ

    (2015)
  • Y. Fuchs et al.

    Live to die another way: modes of programmed cell death and the signals emanating from dying cells

    Nat. Rev. Mol. Cell Biol.

    (2015)
  • L. Galluzzi

    Organelle-specific initiation of cell death

    Nat. Cell Biol.

    (2014)
  • M. Conrad

    Regulated necrosis: disease relevance and therapeutic opportunities

    Nat. Rev. Drug. Discov.

    (2016)
  • L. Galluzzi

    Regulated cell death and adaptive stress responses

    Cell Mol Life Sci.

    (2016)
  • R.C. Taylor

    Apoptosis: controlled demolition at the cellular level

    Nat. Rev. Mol. Cell Biol.

    (2008)
  • T. Vanden Berghe

    Regulated necrosis: the expanding network of non-apoptotic cell death pathways

    Nat. Rev. Mol. Cell Biol.

    (2014)
  • M. Bonora

    Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition

    Oncogene

    (2015)
  • A. Linkermann

    Regulated cell death and inflammation: an auto-amplification loop causes organ failure

    Nat. Rev. Immunol.

    (2014)
  • C.P. Baines

    Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death

    Nature

    (2005)
  • A.C. Schinzel

    Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia

    Proc. Natl. Acad. Sci. U.S.A.

    (2005)
  • P. Bernardi

    The mitochondrial permeability transition pore: channel formation by F-ATP synthase, integration in signal transduction, and role in pathophysiology

    Physiol. Rev.

    (2015)
  • N. Tajeddine

    Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death

    Oncogene

    (2008)
  • J.G. Weaver

    Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor

    J. Clin. Invest.

    (2005)
  • C. Datler

    CKMT1 regulates the mitochondrial permeability transition pore in a process that provides evidence for alternative forms of the complex

    J. Cell Sci.

    (2014)
  • S. Alcala

    A high-throughput screening for mammalian cell death effectors identifies the mitochondrial phosphate carrier as a regulator of cytochrome c release

    Oncogene

    (2008)
  • T. Nakagawa

    Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death

    Nature

    (2005)
  • J.E. Kokoszka

    The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore

    Nature

    (2004)
  • Cited by (172)

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