Phosphate is not an absolute requirement for the inhibitory effects of cyclosporin A or cyclophilin D deletion on mitochondrial permeability transition

McGee, Allison; Baines, Christopher P.

doi:10.1042/bj20111881

Cited by 18 publications

(11 citation statements)

References 29 publications

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“…However, pore regulation by P i has recently been reappraised, as the entire regulatory action of CypD, and thereby CsA, has been suggested to be P i dependent (38). However, this hypothesis is in direct contrast to a recent report by Baines et al in which P i had absolutely no effect in Ppif null or CsA-inhibited pore opening (74), a result that is supported by results from Halestrap’s group who found that P i actually enhanced MPTP opening, but independent of CsA (73). Despite the potential effect of P i , the PiC itself has been suggested to be either an effector of the MPTP, or possibly even a structural component (75).…”

Section: Phosphate Carrier (Pic)contrasting

confidence: 79%

Physiologic Functions of Cyclophilin D and the Mitochondrial Permeability Transition Pore

Elrod

Molkentin

2013

Circ J

217

218

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This review focuses on the role of cyclophilin D (CypD) as a prominent mediator of the mitochondrial permeability transition pore (MPTP) and subsequent effects on cardiovascular physiology and pathology. Although a great number of reviews have been written on the MPTP and its effects on cell death, we focus on the biology surrounding CypD itself and the non-cell death physiologic functions of the MPTP. A greater understanding of the physiologic functions of the MPTP and its regulation by CypD will likely suggest novel therapeutic approaches for cardiovascular disease, both dependent and independent of programmed necrotic cell death mechanisms. red-sensitive mechanism (now known to be the mitochondrial calcium uniporter (MCU), the genetic identity of which was recently discovered 14-16 ) and that permeability transition resulted in the uncoupling of oxidative phosphorylation. The same group followed this discovery with numerous reports detailing the nature of permeability transition and its role in physiology that have largely held to date. The authors concluded in subsequent studies that the channel is gated in a Ca 2+ -specific manner and that its opening imparts permeability to solutes up to 1.5 kDa in size. 17 Hunter et al 18-20 also noted that MPTP open probability is reduced by ADP, adenine nucleotides, and other divalent cations such as Mg 2+ (Sr 2+ , Ba 2+ and Mn 2+ have also been shown to inhibit permeability transition).

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Section: Phosphate Carrier (Pic)contrasting

confidence: 79%

Physiologic Functions of Cyclophilin D and the Mitochondrial Permeability Transition Pore

Elrod

Molkentin

2013

Circ J

217

218

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“…Mouse liver mitochondria were isolated and assayed for PTP opening under energized and de-energized conditions using Dr. Baines’ established protocols 32 . Briefly, 0.25mg/mL mitochondria were placed in swelling buffer containing (in mM) 120 KCl, 10 Tris/HCl, and 5 KH 2 PO 4 (pH 7.4), with (energized) or without (de-energized) 5 succinate (separate pilot experiments with glutamate/malate yielded similar results).…”

Section: Methodsmentioning

confidence: 99%

Reduction of Early Reperfusion Injury With the Mitochondria-Targeting Peptide Bendavia

Brown

Hale

Baines

et al. 2013

J Cardiovasc Pharmacol Ther

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We recently showed that Bendavia, a novel mitochondria-targeting peptide, reduced infarction and no-reflow across several experimental models. The purpose of this study was to determine the therapeutic timing and mechanism of action that underlie Bendavia’s cytoprotective property. In rabbits exposed to in vivo ischemia/reperfusion (30/180 min), Bendavia administered 20 min prior to reperfusion (0.05mg/kg/hr, i.v.) reduced myocardial infarct size by ~50% when administered for either 1 or 3 hours of reperfusion. However, when Bendavia perfusion began just 10 min after the onset of reperfusion, the protection against infarction and no–reflow was completely lost, indicating that the mechanism of protection is occurring early in reperfusion. Experiments in isolated mouse liver mitochondria found no discernible effect of Bendavia on blocking the permeability transition pore, and studies in isolated heart mitochondria showed no effect of Bendavia on respiratory rates. As Bendavia significantly lowered reactive oxygen species (ROS) levels in isolated heart mitochondria, the ROS-scavenging capacity of Bendavia was compared to well-known ROS scavengers using in vitro (cell-free) systems that enzymatically generate ROS. Across doses ranging from 1nM to 1mM, Bendavia showed no discernible ROS-scavenging properties, clearly differentiating itself from prototypical scavengers. In conclusion, Bendavia is a promising candidate to reduce cardiac injury when present at onset of reperfusion, but not after reperfusion has already commenced. Given that both infarction and no-reflow are related to increased cellular ROS, Bendavia’s protective mechanism of action likely involves reduced ROS generation (as opposed to augmented scavenging) by endothelial and myocyte mitochondria.

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“…4,5 The mechanisms whereby CypD deficiency prevents MPTP activation are under investigation and not established yet. 6 - 8 …”

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confidence: 99%

Effects of Oxidative Alcohol Metabolism on the Mitochondrial Permeability Transition Pore and Necrosis in a Mouse Model of Alcoholic Pancreatitis

et al. 2013

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BACKGROUND & AIMS Opening of the mitochondrial permeability transition pore (MPTP) causes loss of the mitochondrial membrane potential (ΔΨm) and, ultimately, adenosine triphosphate depletion and necrosis. Cells deficient in cyclophilin D (CypD), a component of the MPTP, are resistant to MPTP opening, loss of ΔΨm, and necrosis. Alcohol abuse is a major risk factor for pancreatitis and is believed to sensitize the pancreas to stressors, by poorly understood mechanisms. We investigated the effects of ethanol on the pancreatic MPTP, the mechanisms of these effects, and their role in pancreatitis. METHODS We measured ΔΨm in mouse pancreatic acinar cells incubated with ethanol alone and in combination with physiologic and pathologic concentrations of cholecystokinin-8 (CCK). To examine the role of MPTP, we used ex vivo and in vivo models of pancreatitis, induced in wild-type and CypD−/− mice by a combination of ethanol and CCK. RESULTS Ethanol reduced basal ΔΨm and converted a transient depolarization, induced by physiologic concentrations of CCK, into a sustained decrease in ΔΨm, resulting in reduced cellular adenosine triphosphate and increased necrosis. The effects of ethanol and CCK were mediated by MPTP because they were not observed in CypD−/− acinar cells. Ethanol and CCK activated MPTP through different mechanisms— ethanol by reducing the ratio of oxidized nicotinamide adenine dinucleotide to reduced nicotinamide adenine dinucleotide, as a result of oxidative metabolism, and CCK by increasing cytosolic Ca2+. CypD−/− mice developed a less-severe form of pancreatitis after administration of ethanol and CCK. CONCLUSIONS Oxidative metabolism of ethanol sensitizes pancreatic mitochondria to activate MPTP, leading to mitochondrial failure; this makes the pancreas susceptible to necrotizing pancreatitis.

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Phosphate is not an absolute requirement for the inhibitory effects of cyclosporin A or cyclophilin D deletion on mitochondrial permeability transition

Cited by 18 publications

References 29 publications

Physiologic Functions of Cyclophilin D and the Mitochondrial Permeability Transition Pore

Physiologic Functions of Cyclophilin D and the Mitochondrial Permeability Transition Pore

Reduction of Early Reperfusion Injury With the Mitochondria-Targeting Peptide Bendavia

Effects of Oxidative Alcohol Metabolism on the Mitochondrial Permeability Transition Pore and Necrosis in a Mouse Model of Alcoholic Pancreatitis

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