Abstract 1197: The role of mitochondrial permeability transition pore complex proteins VDAC1, ANT, and cyclophilin D in prednisolone-induced apoptosis in B-Lineage acute lymphoblastic leukemia (ALL)

2010 ◽  
Author(s):  
Nan Jiang ◽  
Grace Shi Min Koh ◽  
Shirley Kow Yin Kham ◽  
Fook Tim Chew ◽  
Allen Eng Juh Yeoh
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Lymphoblastic Leukemia ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Permeability Transition Pore Complex ◽  
B Lineage ◽  
Induced Apoptosis

Abstract P234: S-nitrosylation of Cyclophilin D Attenuates Mitochondrial Permeability Transition Pore Opening: A Critical Role for Cysteine 203 Residue

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Tiffany T Nguyen ◽  
Mark V Stevens ◽  
Mark J Kohr ◽  
Charles Steenbergen ◽  
Michael N Sack ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Protective Role ◽  
Nitric Oxide Donor ◽  
Cyclophilin D ◽  
Mitochondrial Permeability ◽  
Mptp Opening

S-nitrosylation (SNO), a reversible, redox-dependent post-translational modification, has emerged as an important mechanism for dynamic regulation of many proteins. Our previous studies have shown that protein S-nitrosylation (SNO) plays a protective role in myocardial ischemia/reperfusion (IR) injury. The primary mediator of cell death in I/R injury is activation of the mitochondrial permeability transition pore (mPTP). Using a proteomic approach, we have previously found that cyclophilin D (CypD), a critical mPTP regulator, can be SNO on cysteine 203 (C203). To investigate whether SNO of CypD might attenuate mPTP activation, we mutated cysteine 203 of CypD, to a serine residue (C203S) and determined its effects on mPTP opening by assessing H 2 O 2 -induced mPTP opening using the calcein AM-cobalt chloride quenching method. Treatment of CypD -/- mouse embryonic fibroblasts (MEFs) with H 2 O 2 resulted loss in an ≈50 % loss of mPTP opening as compared to WT MEFs (n=5, p<0.05), consistent with the protective role of CypD in mPTP activation. Addition of a nitric oxide donor, GSNO, to CypD -/- MEFs did not further reduce mPTP opening; however, WT MEFs treated GSNO attenuated mPTP opening by half. To elucidate the role of SNO of C203 on CypD, we infected CypD -/- MEFs with a C203S-CypD vector. C203S-CypD re-constituted MEFs were also resistant to mPTP opening in the presence or absence of GSNO. This suggests that C203 is required for mPTP activation. To determine whether in vivo expression of C203S-CypD would alter mPTP opening, we generated adenovirus vectors encoding WT CypD or mutated C203S-CypD and injected these viral particles into CypD -/- mice via tail-vein. Mitochondria isolated from livers of CypD -/- mice or mice expressing C203S-CypD were resistant to Ca 2+ -induced swelling as compared to WT CypD reconstituted mice. In summary, our results indicate that C203 of CypD is required for mPTP opening and for the first time shows that SNO of C203 on CypD acts to attenuate mPTP activation.

scholarly journals The role of the mitochondria in apoptosis induced by 7β-hydroxycholesterol and cholesterol-5β,6β-epoxide

2005 ◽  
Vol 94 (4) ◽  
pp. 519-525 ◽  
Author(s):  
Lisa Ryan ◽  
Yvonne C. O'Callaghan ◽  
Nora M. O'Brien
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Apoptotic Pathways ◽  
Induced Apoptosis

Oxysterols are oxygenated derivatives of cholesterol that may be formed endogenously or absorbed from the diet. Significant amounts of oxysterols have frequently been identified in foods of animal origin, in particular highly processed foods. To date, oxysterols have been shown to possess diverse biological activities; however, recent attention has focused on their potential role in the development of atherosclerosis. Oxysterols have been reported to induce apoptosis in cells of the arterial wall, a primary process in the development of atheroma. The aim of the present study was to identify the role of the mitochondria in the apoptotic pathways induced by the oxysterols 7β-hydroxycholesterol (7β-OH) and cholesterol-5β,6β-epoxide (β-epoxide) in U937 cells. To this end, we investigated the effects of these oxysterols on mitochondrial membrane potential, caspase-8 activity, the mitochondrial permeability transition pore and cytochrome c release. 7β-OH-induced apoptosis was associated with a loss in mitochondrial membrane potential after 2 h, accompanied by cytochrome c release from the mitochondria into the cytosol after 16 h. Pre-treatment with a range of inhibitors of the mitochondrial permeability transition pore protected against 7β-OH-induced cell death. In contrast, β-epoxide induced a slight increase in caspase-8 activity but had no effect on mitochondrial membrane potential or cytochrome c release. The present results confirm that 7β-OH-induced apoptosis occurs via the mitochondrial pathway and highlights differences in the apoptotic pathways induced by 7β-OH and β-epoxide in U937 cells.

Abstract 168: Resveratrol Translocates Gsk-3β To Mitochondria And Protects The Heart At Reperfusion By Targeting The Mitochondrial Permeability Transition Pore

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jinkun Xi ◽  
Huihua Wang ◽  
Guillaume Chanoit ◽  
Guang Cheng ◽  
Robert A Mueller ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Risk Zone ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Gsk 3Β

Although resveratrol has been demonstrated to be cardioprotective, the detailed cellular and molecular mechanisms that mediate the protection remain elusive. We aimed to determine if resveratrol protects the heart at reperfusion by modulating the mitochondrial permeability transition pore (mPTP) opening through glycogen synthase kinase 3β (GSK-3β). Resveratrol (10μM) given at reperfusion reduced infarct size (12.2 ± 2.5 % of risk zone vs. 37.9 ± 3.1 % of risk zone in control, n = 6) in isolated rat hearts subjected to 30 min regional ischemia followed by 2 h of reperfusion, an effect that was abrogated by the mPTP opener atractyloside (30.9 ± 8.1 % of risk zone), implying that resveratrol may protect the heart at reperfusion by modulating the mPTP opening. To define the signaling mechanism underlying the action of resveratrol, we determined GSK-3β activity by measuring its phosphorylation at Ser 9 . Resveratrol significantly enhanced GSK-3β phosphorylation upon reperfusion (225.2 ± 30.0 % of control at 5 min of reperfusion). Further experiments showed that resveratrol induces translocation of GSK-3β to mitochondria and translocated GSK-3β interacts with the mPTP component cyclophilin D but not VDAC (the voltage-dependent anion channel) or ANT (the adenine nucleotide translocator) in cardiac mitochondria. Taken together, these data suggest that resveratrol prevents myocardial reperfusion injury by targeting the mPTP opening via GSK-3β. Translocation of GSK-3β to mitochondria and its interaction with the mPTP component cyclophilin D may serve as an essential mechanism that mediates the protective effect of resveratrol on reperfusion injury.

Chronic Tempol treatment restores pharmacological preconditioning in the senescent rat heart

2013 ◽  
Vol 304 (5) ◽  
pp. H649-H659 ◽  
Author(s):  
Jiang Zhu ◽  
Mario J. Rebecchi ◽  
Qiang Wang ◽  
Peter S. A. Glass ◽  
Peter R. Brink ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Mitochondrial Permeability ◽  
Anesthetic Preconditioning ◽  
Permeability Transition Pore Opening ◽  
Pore Opening

Cardioprotective effects of anesthetic preconditioning and cyclosporine A (CsA) are lost with aging. To extend our previous work and address a possible mechanism underlying age-related differences, we investigated the role of oxidative stress in the aging heart by treating senescent animals with the oxygen free radical scavenger Tempol. Old male Fischer 344 rats (22–24 mo) were randomly assigned to control or Tempol treatment groups for 2 or 4 wk (T×2wk and T×4wk, respectively). Rats received isoflurane 30 min before ischemia-reperfusion injury or CsA just before reperfusion. Myocardial infarction sizes were significantly reduced by isoflurane or CsA in the aged rats treated with Tempol (T×4wk) compared with old control rats. In other experiments, young (4–6 mo) and old rats underwent either chronic Tempol or vehicle treatment, and the levels of myocardial protein oxidative damage, antioxidant enzymes, mitochondrial Ca2+ uptake, cyclophilin D protein, and mitochondrial permeability transition pore opening times were measured. T×4wk significantly increased MnSOD enzyme activity, GSH-to-GSSH ratios, MnSOD protein level, mitochondrial Ca2+ uptake capacity, reduced protein nitrotyrosine levels, and normalized cyclophilin D protein expression in the aged rat heart. T×4wk also significantly prolonged mitochondrial permeability transition pore opening times induced by reactive oxygen species in old cardiomyocytes. Our studies demonstrate that 4 wk of Tempol pretreatment restores anesthetic preconditioning and cardioprotection by CsA in the old rat and that this is associated with decreased oxidative stress and improved mitochondrial function. Our results point to a new protective strategy for the ischemic myocardium in the high-risk older population.

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