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

Oncogene volume 34, pages 1475–1486 (2015)Cite this article

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A Corrigendum to this article was published on 19 March 2015

This article has been updated

Abstract

The term mitochondrial permeability transition (MPT) is commonly used to indicate an abrupt increase in the permeability of the inner mitochondrial membrane to low molecular weight solutes. Widespread MPT has catastrophic consequences for the cell, de facto marking the boundary between cellular life and death. MPT results indeed in the structural and functional collapse of mitochondria, an event that commits cells to suicide via regulated necrosis or apoptosis. MPT has a central role in the etiology of both acute and chronic diseases characterized by the loss of post-mitotic cells. Moreover, cancer cells are often relatively insensitive to the induction of MPT, underlying their increased resistance to potentially lethal cues. Thus, intense efforts have been dedicated not only at the understanding of MPT in mechanistic terms, but also at the development of pharmacological MPT modulators. In this setting, multiple mitochondrial and extramitochondrial proteins have been suspected to critically regulate the MPT. So far, however, only peptidylprolyl isomerase F (best known as cyclophilin D) appears to constitute a key component of the so-called permeability transition pore complex (PTPC), the supramolecular entity that is believed to mediate MPT. Here, after reviewing the structural and functional features of the PTPC, we summarize recent findings suggesting that another of its core components is represented by the c subunit of mitochondrial ATP synthase.

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  • 19 March 2014

    This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue

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Acknowledgements

This article was supported by: the Italian Association for Cancer Research (AIRC); Telethon (GGP11139B); local funds from the University of Ferrara; the Italian Ministry of Education, University and Research (COFIN, FIRB and Futuro in Ricerca); and an Italian Ministry of Health grant to PP. MRW is supported by the Polish National Science Center (UMO-2011/11/M/NZ3/02128), Polish Ministry of Science and Higher Education grant W100/HFSC/2011 and BIO-IMAGing in Research Innovation and Education (FP7-REGPOT-2010-1). CC is supported by the Hungarian Academy of Sciences (MTA-SE Lendület Neurobiochemistry Research Division grant 95003) and the Hungarian Scientific Research Fund (grant K 100918). GK is supported by the Ligue contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR); Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI).

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  1. L Galluzzi and P Pinton: These authors share senior co-authorship.

Authors and Affiliations

  1. Department of Morphology, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), Surgery and Experimental Medicine, Interdisciplinary Centre for the Study of Inflammation (ICSI), University of Ferrara, Ferrara, Italy

    M Bonora & P Pinton

  2. Department of Biochemistry, Nencki Institute of Experimental Biology, Warsaw, Poland

    M R Wieckowski

  3. Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary

    C Chinopoulos

  4. Equipe 11 labelisée par la Ligue Nationale contre le cancer, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France

    O Kepp, G Kroemer & L Galluzzi

  5. Université Paris Descartes/Paris 5, Sorbonne Paris Cité, Paris, France

    O Kepp, G Kroemer & L Galluzzi

  6. Metabolomics and Cell Biology platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif, France

    O Kepp & G Kroemer

  7. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    G Kroemer

  8. Gustave Roussy Comprehensive Cancer Center, Villejuif, France

    L Galluzzi

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Bonora, M., Wieckowski, M., Chinopoulos, C. et al. Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition. Oncogene 34, 1475–1486 (2015). https://doi.org/10.1038/onc.2014.96

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