Authors: Massimo Bonora, Angela Bononi, Elena De Marchi, Carlotta Giorgi, Magdalena Lebiedzinska, Saverio Marchi, Simone Patergnani, Alessandro Rimessi, Jan M. Suski, Aleksandra Wojtala, Mariusz R. Wieckowski, Guido Kroemer, Lorenzo Galluzzi and Paolo Pinton

Massimo Bonora

Department of Morphology, Surgery and Experimental Medicine; Section of General Pathology; Interdisciplinary Center for the Study of Inflammation (ICSI); Laboratory for Technologies of Advanced Therapies (LTTA); University of Ferrara; Ferrara, Italy

Angela Bononi

Department of Morphology, Surgery and Experimental Medicine; Section of General Pathology; Interdisciplinary Center for the Study of Inflammation (ICSI); Laboratory for Technologies of Advanced Therapies (LTTA); University of Ferrara; Ferrara, Italy

Elena De Marchi

Department of Morphology, Surgery and Experimental Medicine; Section of General Pathology; Interdisciplinary Center for the Study of Inflammation (ICSI); Laboratory for Technologies of Advanced Therapies (LTTA); University of Ferrara; Ferrara, Italy

Carlotta Giorgi

Department of Morphology, Surgery and Experimental Medicine; Section of General Pathology; Interdisciplinary Center for the Study of Inflammation (ICSI); Laboratory for Technologies of Advanced Therapies (LTTA); University of Ferrara; Ferrara, Italy

Magdalena Lebiedzinska

Department of Morphology, Surgery and Experimental Medicine; Section of General Pathology; Interdisciplinary Center for the Study of Inflammation (ICSI); Laboratory for Technologies of Advanced Therapies (LTTA); University of Ferrara; Ferrara, Italy; Department of Biochemistry; Nencki Institute of Experimental Biology; Warsaw, Poland

Saverio Marchi

Department of Morphology, Surgery and Experimental Medicine; Section of General Pathology; Interdisciplinary Center for the Study of Inflammation (ICSI); Laboratory for Technologies of Advanced Therapies (LTTA); University of Ferrara; Ferrara, Italy

Simone Patergnani

Department of Morphology, Surgery and Experimental Medicine; Section of General Pathology; Interdisciplinary Center for the Study of Inflammation (ICSI); Laboratory for Technologies of Advanced Therapies (LTTA); University of Ferrara; Ferrara, Italy

Alessandro Rimessi

Department of Morphology, Surgery and Experimental Medicine; Section of General Pathology; Interdisciplinary Center for the Study of Inflammation (ICSI); Laboratory for Technologies of Advanced Therapies (LTTA); University of Ferrara; Ferrara, Italy

Jan M. Suski

Department of Morphology, Surgery and Experimental Medicine; Section of General Pathology; Interdisciplinary Center for the Study of Inflammation (ICSI); Laboratory for Technologies of Advanced Therapies (LTTA); University of Ferrara; Ferrara, Italy; Department of Biochemistry; Nencki Institute of Experimental Biology; Warsaw, Poland

Aleksandra Wojtala

Department of Biochemistry; Nencki Institute of Experimental Biology; Warsaw, Poland

Mariusz R. Wieckowski

Department of Biochemistry; Nencki Institute of Experimental Biology; Warsaw, Poland
These authors share senior co-authorship.

Guido Kroemer

Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France; U848; INSERM; Villejuif, France; Metabolomics Platform; Institut Gustave Roussy; Villejuif, France; Equipe 11 Labelisée par la Ligue Contre le cancer; Centre de Recherche des Cordeliers; Paris, France; Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP; Paris, France
These authors share senior co-authorship.

Lorenzo Galluzzi

Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France; Institut Gustave Roussy; Villejuif, France
These authors share senior co-authorship.

Paolo Pinton

Corresponding author: pnp@unife.it
Department of Morphology, Surgery and Experimental Medicine; Section of General Pathology; Interdisciplinary Center for the Study of Inflammation (ICSI); Laboratory for Technologies of Advanced Therapies (LTTA); University of Ferrara; Ferrara, Italy
These authors share senior co-authorship.

Abstract:
The term “mitochondrial permeability transition” (MPT) refers to an abrupt increase in the permeability of the inner mitochondrial membrane to low molecular weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse of the organelle. Thus, MPT can initiate mitochondrial outer membrane permeabilization (MOMP), promoting the activation of the apoptotic caspase cascade as well as of caspase-independent cell death mechanisms. MPT appears to be mediated by the opening of the so-called “permeability transition pore complex” (PTPC), a poorly characterized and versatile supramolecular entity assembled at the junctions between the inner and outer mitochondrial membranes. In spite of considerable experimental efforts, the precise molecular composition of the PTPC remains obscure and only one of its constituents, cyclophilin D (CYPD), has been ascribed with a crucial role in the regulation of cell death. Conversely, the results of genetic experiments indicate that other major components of the PTPC, such as voltage-dependent anion channel (VDAC) and adenine nucleotide translocase (ANT), are dispensable for MPT-driven MOMP. Here, we demonstrate that the c subunit of the F_O ATP synthase is required for MPT, mitochondrial fragmentation and cell death as induced by cytosolic calcium overload and oxidative stress in both glycolytic and respiratory cell models. Our results strongly suggest that, similar to CYPD, the c subunit of the F_O ATP synthase constitutes a critical component of the PTPC.

Received: January 6, 2013; Accepted: January 13, 2013; Published Online: January 23, 2013

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