Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition.
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 FO 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 FO ATP synthase constitutes a critical component of the PTPC.
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.
Massimo
M
Bonora
Angela
A
Bononi
Elena
E
De Marchi
Carlotta
C
Giorgi
Magdalena
M
Lebiedzinska
Saverio
S
Marchi
Simone
S
Patergnani
Alessandro
A
Rimessi
Jan M
JM
Suski
Aleksandra
A
Wojtala
Mariusz R
MR
Wieckowski
Guido
G
Kroemer
Lorenzo
L
Galluzzi
Paolo
P
Pinton
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000737:chemistry / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000737:chemistry / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D025261:Mitochondrial Proton-Translocating ATPases / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress; D061251:Primary Cell Culture; D051381:Rats; D050994:Voltage-Dependent Anion Channels / Q000737:chemistry / Q000378:metabolism
D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D050994:Voltage-Dependent Anion Channels; D000226:Mitochondrial ADP, ATP Translocases; C103607:mitochondrial ATPase subunit c; D025261:Mitochondrial Proton-Translocating ATPases; D021983:Cyclophilins
ATP5G1; apoptosis; caspases; cytochrome c; mitochondrial respiratory chain; p53; permeability transition pore (PTP)