scholarly journals Defining the molecular mechanisms of the mitochondrial permeability transition through genetic manipulation of F-ATP synthase

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Andrea Carrer ◽  
Ludovica Tommasin ◽  
Justina Šileikytė ◽  
Francesco Ciscato ◽  
Riccardo Filadi ◽  
...  
Keyword(s):  
Atp Synthase ◽  
Molecular Mechanisms ◽  
Mitochondrial Permeability Transition ◽  
Genetic Manipulation ◽  
Adenine Nucleotide ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Channel Formation ◽  
Intact Cells ◽  
Mitochondrial Permeability

AbstractF-ATP synthase is a leading candidate as the mitochondrial permeability transition pore (PTP) but the mechanism(s) leading to channel formation remain undefined. Here, to shed light on the structural requirements for PTP formation, we test cells ablated for g, OSCP and b subunits, and ρ0 cells lacking subunits a and A6L. Δg cells (that also lack subunit e) do not show PTP channel opening in intact cells or patch-clamped mitoplasts unless atractylate is added. Δb and ΔOSCP cells display currents insensitive to cyclosporin A but inhibited by bongkrekate, suggesting that the adenine nucleotide translocator (ANT) can contribute to channel formation in the absence of an assembled F-ATP synthase. Mitoplasts from ρ0 mitochondria display PTP currents indistinguishable from their wild-type counterparts. In this work, we show that peripheral stalk subunits are essential to turn the F-ATP synthase into the PTP and that the ANT provides mitochondria with a distinct permeability pathway.

scholarly journals Cyclophilin-D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosis

2004 ◽  
Vol 383 (1) ◽  
pp. 101-109 ◽  
Author(s):  
Yanmin LI ◽  
Nicholas JOHNSON ◽  
Michela CAPANO ◽  
Mina EDWARDS ◽  
Martin CROMPTON
Keyword(s):  
Oxidative Stress ◽  
Cell Injury ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Intact Cells ◽  
Inner Membrane ◽  
Mitochondrial Permeability ◽  
Apoptosis And Necrosis

Cyclophilin-D is a peptidylprolyl cis–trans isomerase of the mitochondrial matrix. It is involved in mitochondrial permeability transition, in which the adenine nucleotide translocase of the inner membrane is transformed from an antiporter to a non-selective pore. The permeability transition has been widely considered as a mechanism in both apoptosis and necrosis. The present study examines the effects of cyclophilin-D on the permeability transition and lethal cell injury, using a neuronal (B50) cell line stably overexpressing cyclophilin-D in mitochondria. Cyclophilin-D overexpression rendered isolated mitochondria far more susceptible to the permeability transition induced by Ca2+ and oxidative stress. Similarly, cyclophilin-D overexpression brought forward the onset of the permeability transition in intact cells subjected to oxidative stress. In addition, in the absence of stress, the mitochondria of cells overexpressing cyclophilin-D maintained a lower inner-membrane potential than those of normal cells. All these effects of cyclophilin-D overexpression were abolished by cyclosporin A. It is concluded that cyclophilin-D promotes the permeability transition in B50 cells. However, cyclophilin-D overexpression had opposite effects on apoptosis and necrosis; whereas NO-induced necrosis was promoted, NO- and staurosporine-induced apoptosis were inhibited. These findings indicate that the permeability transition leads to cell necrosis, but argue against its involvement in apoptosis.

scholarly journals The HIV-1 Viral Protein R Induces Apoptosis via a Direct Effect on the Mitochondrial Permeability Transition Pore

2000 ◽  
Vol 191 (1) ◽  
pp. 33-46 ◽  
Author(s):  
Etienne Jacotot ◽  
Luigi Ravagnan ◽  
Markus Loeffler ◽  
Karine F. Ferri ◽  
Helena L.A. Vieira ◽  
...  
Keyword(s):  
Direct Effect ◽  
Viral Protein ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Voltage Dependent Anion Channel ◽  
Intact Cells ◽  
Viral Protein R ◽  
Hiv 1

Viral protein R (Vpr) encoded by HIV-1 is a facultative inducer of apoptosis. When added to intact cells or purified mitochondria, micromolar and submicromolar doses of synthetic Vpr cause a rapid dissipation of the mitochondrial transmembrane potential (ΔΨm), as well as the mitochondrial release of apoptogenic proteins such as cytochrome c or apoptosis inducing factor. The same structural motifs relevant for cell killing are responsible for the mitochondriotoxic effects of Vpr. Both mitochondrial and cytotoxic Vpr effects are prevented by Bcl-2, an inhibitor of the permeability transition pore complex (PTPC). Coincubation of purified organelles revealed that nuclear apoptosis is only induced by Vpr when mitochondria are present yet can be abolished by PTPC inhibitors. Vpr favors the permeabilization of artificial membranes containing the purified PTPC or defined PTPC components such as the adenine nucleotide translocator (ANT) combined with Bax. Again, this effect is prevented by addition of recombinant Bcl-2. The Vpr COOH terminus binds purified ANT, as well as a molecular complex containing ANT and the voltage-dependent anion channel (VDAC), another PTPC component. Yeast strains lacking ANT or VDAC are less susceptible to Vpr-induced killing than control cells yet recover Vpr sensitivity when retransfected with yeast ANT or human VDAC. Hence, Vpr induces apoptosis via a direct effect on the mitochondrial PTPC.

scholarly journals FOF1-ATP Synthase Dimers and The Mitochondrial Permeability Transition Pore from Yeast to Mammals

2014 ◽  
Vol 106 (2) ◽  
pp. 3a
Author(s):  
Paolo Bernardi ◽  
Valentina Giorgio ◽  
Michela Carraro ◽  
Sophia von Stockum ◽  
Victoria Burchell ◽  
...  
Keyword(s):  
Atp Synthase ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Fof1 Atp Synthase

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

Oncogene ◽  
2014 ◽  
Vol 34 (12) ◽  
pp. 1475-1486 ◽  
Author(s):  
M Bonora ◽  
M R Wieckowski ◽  
C Chinopoulos ◽  
O Kepp ◽  
G Kroemer ◽  
...  
Keyword(s):  
Cell Death ◽  
Atp Synthase ◽  
Molecular Mechanisms ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Permeability
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