Properties of the Permeability Transition Pore in Mitochondria Devoid of Cyclophilin D*

By E. Basso, Lisa Fante, J. Fowlkes, V. Petronilli, M. Forte, P. Bernardi. Journal of Biological Chemistry, 2005

848 citations recorded by the source corpus.

We have studied the properties of the permeability transition pore (PTP) in mitochondria from the liver of mice where the Ppif gene encoding for mitochondrial Cyclophilin D (CyP-D) had been inactivated. Mitochondria from Ppif–/– mice had no CyP-D and displayed a striking desensitization of the PTP to Ca2+, in that pore opening required about twice the Ca2+ load necessary to open the pore in strain-matched, wild-type mitochondria. Mitochondria lacking CyP-D were insensitive to Cyclosporin A (CsA), which increased the Ca2+ retention capacity only in mitochondria from wild-type mice. The PTP response to ubiquinone 0, depolarization, pH, adenine nucleotides, and thiol oxidants was similar in mitochondria from wild-type and Ppif–/– mice. These experiments demonstrate that (i) the PTP can form and open in the absence of CyP-D, (ii) that CyP-D represents the target for PTP inhibition by CsA, and (iii) that CyP-D modulates the sensitivity of the PTP to Ca2+ but not its regulation by the proton electrochemical gradient, adenine nucleotides, and oxidative stress. These results have major implications for our current understanding of the PTP and its modulation in vitro and in vivo.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4912ed6fed53094a3a4eb475935671aff91438db

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Citations in the corpus

Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death (2007, background): “Although recent genetic studies have confirmed a regulatory role for cyclophilin D in MPT (24,27-29), mice lacking Ant1/2 still exhibit a classical MPT response that was inhibited with cyclosporine A (30).”
Mitochondrial Calcium and the Permeability Transition in Cell Death (2009, background): “Also as predicted by themisfolded protein model, mitochondria from CypD knockout mice are desensitized to Ca induction of the MPT and require much higher Ca to induce mitochondrial swelling [1], which is consistent with the proposed role of CypD as the Ca sensor of the MPT.”
Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. (2006, background): “In addition, CypD-deficient mice are highly resistant to cardiac injury induced by ischemia/ reperfusion, confirming that CypD-dependent MPT regulates some forms of necrotic death [118–121].”
Mitochondria-Ros Crosstalk in the Control of Cell Death and Aging (2011, background): “To find more about the presence of VDAC, ANT, or cyclophilin D in the mPTP, refer to [84–86].”
Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. (2014, background): “It can be raised by protective signaling [through preconditioning (218), cyclosporin A (180, 218), sanglofehrin (89), acidosis (47), cyclophilin D acetylation or its knockout (26, 34, 313, 387)] shown by a green dotted line.”
Mitochondrial calcium signalling and cell death: approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis. (2006, background): “When large quantities of Ca2+ are accumulated in the mitochondrial matrix, Ca2+ interacts with cyclophilin D to induce opening of the PTP [10].”
The role of mitochondria in apoptosis. (2008, background): “org membrane can lead to matrix swelling, causing the rupture of the outer mitochondrial membrane and release of cytochrome c (53, 54).”
Neuronal Cell Death. (2018, positive): “In general, opening of mPTP results in necrotic/oncotic cell death due to energy depletion (39, 489).”
Dimers of mitochondrial ATP synthase form the permeability transition pore (2013, background): “The mean ratio between ATP-hydrolyzing and -synthesizing mitochondria was 2.06 ± 0.27 in four independent experiments per condition, an effect that matches the effect of CsA in mouse liver mitochondria (20).”
Cell Death Signaling. (2015, background): “Cyclophilin D (CypD), a peptidyl-proline trans-isomerase, plays a major role in mPT. Mice lacking CypD display defective mPTs (Baines et al. 2005; Basso et al. 2005; Nakagawa et al. 2005; Schinzel et al. 2005) and display diminished tissue damage under conditions of I/R (Baines et al. 2005;…”
p53 opens the mitochondrial permeability transition pore to trigger necrosis (2012, background): “But notably, they remain sensitive to Bcl-2 family-driven apoptosis, emphasizing the two functionally distinct mitochondrial death systems (Baines et al., 2005; Basso et al., 2005; Nakagawa et al., 2005; Schinzel et al., 2005).”
The changing faces of glutathione, a cellular protagonist. (2003, background): “In contrast, the prolyl isomerase cyclophilin D in the mitochondrial matrix is an essential regulator of MPT and the only genetically proven indispensable MPT component (Baines et al., 2005; Basso et al., 2005; Nakagawa et al., 2005; Schinzel et al., 2005).”