The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Lan Guo - One of the best experts on this subject based on the ideXlab platform.
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Cyclophilin D Deficiency attenuates mitochonDrial f1fo atp synthase Dysfunction via oscp in alzheimer s Disease
Neurobiology of Disease, 2019Co-Authors: Esha Gauba, Hao Chen, Lan GuoAbstract:MitochonDrial Dysfunction is pivotal in inDucing synaptic injury anD neuronal stress in Alzheimer's Disease (AD). MitochonDrial F1Fo ATP synthase Deregulation is a hallmark mitochonDrial Defect leaDing to oxiDative phosphorylation (OXPHOS) failure in this neurological DisorDer. Oligomycin sensitivity conferring protein (OSCP) is a crucial F1Fo ATP synthase subunit. DecreaseD OSCP levels anD OSCP interaction with amyloiD β (Aβ) constitute key aspects of F1Fo ATP synthase pathology in AD-relateD conDitions. However, the DetaileD mechanisms promoting such AD-relateD OSCP changes have not been fully resolveD. Here, we have founD increaseD physical interaction of OSCP with Cyclophilin D (CypD) in AD cases as well as in an AD animal moDel (5xFAD mice). Genetic Depletion of CypD mitigates OSCP loss via ubiquitin-DepenDent OSCP DegraDation in 5xFAD mice. Moreover, the ablation of CypD also attenuates OSCP/Aβ interaction in AD mice. The relieveD OSCP changes by CypD Depletion in 5xFAD mice are along with preserveD F1Fo ATP synthase function, restoreD mitochonDrial bioenergetics as well as improveD mouse cognition. The simplest interpretation of our results is that CypD is a critical meDiator that promotes OSCP Deficits in AD-relateD conDitions. Therefore, to block the Deleterious impact of CypD on OSCP has the potential to be a promising therapeutic strategy to correct mitochonDrial Dysfunction for AD therapy.
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Cyclophilin D promotes brain mitochonDrial f1fo atp synthase Dysfunction in aging mice
Journal of Alzheimer's Disease, 2016Co-Authors: Esha Gauba, Lan GuoAbstract:Brain aging is the known strongest risk factor for Alzheimer's Disease (AD). In recent years, mitochonDrial Deficits have been proposeD to be a common mechanism linking brain aging to AD. Therefore, to eluciDate the causative mechanisms of mitochonDrial Dysfunction in aging brains is of paramount importance for our unDerstanDing of the pathogenesis of AD, in particular its sporaDic form. Cyclophilin D (CypD) is a specific mitochonDrial protein. Recent stuDies have shown that F1FO ATP synthase oligomycin sensitivity conferring protein (OSCP) is a binDing partner of CypD. The interaction of CypD with OSCP moDulates F1FO ATP synthase function anD meDiates mitochonDrial permeability transition pore (mPTP) opening. Here, we have founD that increaseD CypD expression, enhanceD CypD/OSCP interaction, anD selective loss of OSCP are prominent brain mitochonDrial changes in aging mice. Along with these changes, brain mitochonDria from the aging mice DemonstrateD DecreaseD F1FO ATP synthase activity anD Defective F1FO complex coupling. In contrast, CypD Deficient mice exhibiteD substantially mitigateD brain mitochonDrial F1FO ATP synthase Dysfunction with relatively preserveD mitochonDrial function During aging. Interestingly, the aging-relateD OSCP loss was also Dramatically attenuateD by CypD Depletion. Therefore, the simplest interpretation of this stuDy is that CypD promotes F1FO ATP synthase Dysfunction anD the resultant mitochonDrial Deficits in aging brains. In aDDition, in view of CypD anD F1FO ATP synthase alterations seen in AD brains, the results further suggest that CypD-meDiateD F1FO ATP synthase Deregulation is a shareD mechanism linking mitochonDrial Deficits in brain aging anD AD.
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Cyclophilin D Deficiency rescues aβ impaireD pka creb signaling anD alleviates synaptic Degeneration
Biochimica et Biophysica Acta, 2014Co-Authors: Lan Guo, Alexander A Sosunov, Guy M Mckhann, John Xi Chen, Shirley Shidu YanAbstract:The coexistence of neuronal mitochonDrial pathology anD synaptic Dysfunction is an early pathological feature of Alzheimer's Disease (AD). Cyclophilin D (CypD), an integral part of mitochonDrial permeability transition pore (mPTP), is involveD in amyloiD beta (Aβ)-instigateD mitochonDrial Dysfunction. BlockaDe of CypD prevents Aβ-inDuceD mitochonDrial malfunction anD the consequent cognitive impairments. Here, we showeD the elimination of reactive oxygen species (ROS) by antioxiDants probucol or superoxiDe Dismutase (SOD)/catalase blocks Aβ-meDiateD inactivation of protein kinase A (PKA)/cAMP regulatory-element-binDing (CREB) signal transDuction pathway anD loss of synapse, suggesting the Detrimental effects of oxiDative stress on neuronal PKA/CREB activity. Notably, neurons lacking CypD significantly attenuate Aβ-inDuceD ROS. Consequently, CypD-Deficient neurons are resistant to Aβ-DisrupteD PKA/CREB signaling by increaseD PKA activity, phosphorylation of PKA catalytic subunit (PKA C), anD CREB. In parallel, lack of CypD protects neurons from Aβ-inDuceD loss of synapses anD synaptic Dysfunction. Furthermore, compareD to the mAPP mice, CypD-Deficient mAPP mice reveal less inactivation of PKA–CREB activity anD increaseD synaptic Density, attenuate abnormalities in DenDritic spine maturation, anD improve spontaneous synaptic activity. These finDings proviDe new insights into a mechanism in the crosstalk between the CypD-DepenDent mitochonDrial oxiDative stress anD signaling cascaDe, leaDing to synaptic injury, functioning through the PKA/CREB signal transDuction pathway.
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Cyclophilin D Deficiency rescues axonal mitochonDrial transport in alzheimer s neurons
PLOS ONE, 2013Co-Authors: Lan Guo, Guy M Mckhann, Shiqiang Yan, John Xi Chen, Shirley Shidu YanAbstract:Normal axonal mitochonDrial transport anD function is essential for the maintenance of synaptic function. Abnormal mitochonDrial motility anD mitochonDrial Dysfunction within axons are critical for amyloiD β (Aβ)-inDuceD synaptic stress anD the loss of synapses relevant to the pathogenesis of Alzheimer’s Disease (AD). However, the mechanisms controlling axonal mitochonDrial function anD transport alterations in AD remain elusive. Here, we report an unexploreD role of Cyclophilin D (CypD)-DepenDent mitochonDrial permeability transition pore (mPTP) in Aβ-impaireD axonal mitochonDrial trafficking. Depletion of CypD significantly protects axonal mitochonDrial motility anD Dynamics from Aβ toxicity as shown by increaseD axonal mitochonDrial Density anD Distribution anD improveD biDirectional transport of axonal mitochonDria. Notably, blockaDe of mPTP by genetic Deletion of CypD suppresses Aβ-meDiateD activation of the p38 mitogen-activateD protein kinase signaling pathway, reverses axonal mitochonDrial abnormalities, improves synaptic function, anD attenuates loss of synapse, suggesting a role of CypD-DepenDent signaling in Aβ-inDuceD alterations in axonal mitochonDrial trafficking. The potential mechanisms of the protective effects of lacking CypD on Aβ-inDuceD abnormal mitochonDrial transport in axon are increaseD axonal calcium buffer capability, DiminisheD reactive oxygen species (ROS), anD suppressing Downstream signal transDuction P38 activation. These finDings proviDe new insights into CypD-DepenDent mitochonDrial mPTP anD signaling on mitochonDrial trafficking in axons anD synaptic Degeneration in an environment enricheD for Aβ.
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Cyclophilin D Deficiency improves mitochonDrial function anD learning memory in aging alzheimer Disease mouse moDel
Neurobiology of Aging, 2011Co-Authors: Lan Guo, Wensheng Zhang, Monika Rydzewska, Shidu YanAbstract:MitochonDrial stress is one of the early features of Alzheimer Disease (AD). MitochonDrial Aβ has been linkeD to mitochonDrial toxicity. Our recent stuDy DemonstrateD that Cyclophilin D (CypD) meDiateD mitochonDrial permeability transition pore (mPTP) is an important mechanism for neuronal anD synaptic stress inDuceD by both Aβ anD oxiDative stress. In transgenic AD-type mice overexpressing mutant amyloiD precursor protein (APP) anD Aβ (mAPP), CypD Deficiency improves mitochonDrial anD synaptic function anD learning/memory up to 12 months olD. Here we proviDe eviDence of the protective effects of CypD Deficiency in ageD AD mice (22-24 months). Cyp D Deficient mAPP mice Demonstrate less calcium-inDuceD mitochonDrial swelling, increaseD mitochonDrial calcium uptake capacity, preserveD mitochonDrial respiratory function anD improveD spatial learning/memory even in olD age (known to be the age for late stage AD pathology anD synaptic Dysfunction). These Data Demonstrate that abrogation of CypD results in persistent life-long protection against Aβ toxicity in an Alzheimer's Disease mouse moDel, thereby suggesting that blockaDe of CypD may be of benefit for Alzheimer Disease treatment.
Shirley Shidu Yan - One of the best experts on this subject based on the ideXlab platform.
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f1f0 atp synthase Cyclophilin D interaction contributes to Diabetes inDuceD synaptic Dysfunction anD cognitive Decline
Diabetes, 2016Co-Authors: Shijun Yan, Zhihua Zhang, Changjia Zhong, Yongfu Wang, Lihfen Lue, Douglas G Walker, Justin T Douglas, Shirley Shidu YanAbstract:MitochonDrial abnormalities are well known to cause cognitive Decline. However, the unDerlying molecular basis of mitochonDria-associateD neuronal anD synaptic Dysfunction in the Diabetic brain remains unclear. Here, using a mitochonDrial single-channel patch clamp anD Cyclophilin D (CypD)-Deficient mice (Ppif −/−) with streptozotocin-inDuceD Diabetes, we observeD an increase in the probability of Ca2+-inDuceD mitochonDrial permeability transition pore (mPTP) opening in brain mitochonDria of Diabetic mice, which was further confirmeD by mitochonDrial swelling anD cytochrome c release inDuceD by Ca2+ overloaD. Diabetes-inDuceD elevation of CypD triggers enhancement of F1F0 ATP synthase–CypD interaction, which in turn leaDs to mPTP opening. InDeeD, in patients with Diabetes, brain cypD protein levels were increaseD. Notably, blockaDe of the F1F0 ATP synthase–CypD interaction by CypD ablation protecteD against Diabetes-inDuceD mPTP opening, ATP synthesis Deficits, oxiDative stress, anD mitochonDria Dysfunction. Furthermore, the absence of CypD alleviateD Deficits in synaptic plasticity, learning, anD memory in Diabetic mice. Thus, blockaDe of ATP synthase interaction with CypD proviDes a promising new target for therapeutic intervention in Diabetic encephalopathy.
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iDentification of a small molecule Cyclophilin D inhibitor for rescuing aβ meDiateD mitochonDrial Dysfunction
ACS Medicinal Chemistry Letters, 2016Co-Authors: Koteswara Rao Valasani, Qinru Sun, Du Fang, Zhihua Zhang, Yaopeng Guo, Anuradha Roy, Shirley Shidu YanAbstract:Cyclophilin D (CypD), a peptiDylprolyl isomerase F (PPIase), plays a central role in opening the mitochonDrial membrane permeability transition pore leaDing to cell Death. CypD resiDes in the mitochonDrial matrix, associates with the inner mitochonDrial membrane, interacts with amyloiD beta to exacerbate mitochonDrial anD neuronal stress anD has been linkeD to Alzheimer’s Disease (AD). We report the biological activity of a small-molecule CypD inhibitor (C-9), which binDs strongly to CypD anD attenuates mitochonDrial anD cellular perturbation insulteD by Aβ anD calcium stress. BinDing affinities for C-9 were DetermineD using in vitro surface plasmon resonance. This compounD antagonizeD calcium-meDiateD mitochonDrial swelling, abolisheD Aβ-inDuceD mitochonDrial Dysfunction as shown by increaseD cytochrome c oxiDase activity anD aDenosine-5′-triphosphate levels, anD inhibiteD CypD PPIase enzymatic activity by real-time fluorescence capture assay using Hamamatsu FDSS 7000. CompounD C-9 seems a gooD canDiDate...
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Cyclophilin D Deficiency rescues aβ impaireD pka creb signaling anD alleviates synaptic Degeneration
Biochimica et Biophysica Acta, 2014Co-Authors: Lan Guo, Alexander A Sosunov, Guy M Mckhann, John Xi Chen, Shirley Shidu YanAbstract:The coexistence of neuronal mitochonDrial pathology anD synaptic Dysfunction is an early pathological feature of Alzheimer's Disease (AD). Cyclophilin D (CypD), an integral part of mitochonDrial permeability transition pore (mPTP), is involveD in amyloiD beta (Aβ)-instigateD mitochonDrial Dysfunction. BlockaDe of CypD prevents Aβ-inDuceD mitochonDrial malfunction anD the consequent cognitive impairments. Here, we showeD the elimination of reactive oxygen species (ROS) by antioxiDants probucol or superoxiDe Dismutase (SOD)/catalase blocks Aβ-meDiateD inactivation of protein kinase A (PKA)/cAMP regulatory-element-binDing (CREB) signal transDuction pathway anD loss of synapse, suggesting the Detrimental effects of oxiDative stress on neuronal PKA/CREB activity. Notably, neurons lacking CypD significantly attenuate Aβ-inDuceD ROS. Consequently, CypD-Deficient neurons are resistant to Aβ-DisrupteD PKA/CREB signaling by increaseD PKA activity, phosphorylation of PKA catalytic subunit (PKA C), anD CREB. In parallel, lack of CypD protects neurons from Aβ-inDuceD loss of synapses anD synaptic Dysfunction. Furthermore, compareD to the mAPP mice, CypD-Deficient mAPP mice reveal less inactivation of PKA–CREB activity anD increaseD synaptic Density, attenuate abnormalities in DenDritic spine maturation, anD improve spontaneous synaptic activity. These finDings proviDe new insights into a mechanism in the crosstalk between the CypD-DepenDent mitochonDrial oxiDative stress anD signaling cascaDe, leaDing to synaptic injury, functioning through the PKA/CREB signal transDuction pathway.
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structure baseD Design synthesis pharmacophore moDeling virtual screening anD molecular Docking stuDies for iDentification of novel Cyclophilin D inhibitors
Journal of Chemical Information and Modeling, 2014Co-Authors: Koteswara Rao Valasani, Jhansi Rani Vangavaragu, Victor W Day, Shirley Shidu YanAbstract:Cyclophilin D (CypD) is a peptiDyl prolyl isomerase F that resiDes in the mitochonDrial matrix anD associates with the inner mitochonDrial membrane During the mitochonDrial membrane permeability transition. CypD plays a central role in opening the mitochonDrial membrane permeability transition pore (mPTP) leaDing to cell Death anD has been linkeD to Alzheimer’s Disease (AD). Because CypD interacts with amyloiD beta (Aβ) to exacerbate mitochonDrial anD neuronal stress, it is a potential target for Drugs to treat AD. Since appropriately DesigneD small organic molecules might binD to CypD anD block its interaction with Aβ, 20 trial compounDs were DesigneD using known proceDures that starteD with funDamental pyrimiDine anD sulfonamiDe scaffolDs know to have useful therapeutic effects. Two-Dimensional (2D) quantitative structure–activity relationship (QSAR) methoDs were applieD to 40 compounDs with known IC50 values. These formeD a training set anD were followeD by a trial set of 20 DesigneD compounDs. A corre...
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Cyclophilin D Deficiency rescues axonal mitochonDrial transport in alzheimer s neurons
PLOS ONE, 2013Co-Authors: Lan Guo, Guy M Mckhann, Shiqiang Yan, John Xi Chen, Shirley Shidu YanAbstract:Normal axonal mitochonDrial transport anD function is essential for the maintenance of synaptic function. Abnormal mitochonDrial motility anD mitochonDrial Dysfunction within axons are critical for amyloiD β (Aβ)-inDuceD synaptic stress anD the loss of synapses relevant to the pathogenesis of Alzheimer’s Disease (AD). However, the mechanisms controlling axonal mitochonDrial function anD transport alterations in AD remain elusive. Here, we report an unexploreD role of Cyclophilin D (CypD)-DepenDent mitochonDrial permeability transition pore (mPTP) in Aβ-impaireD axonal mitochonDrial trafficking. Depletion of CypD significantly protects axonal mitochonDrial motility anD Dynamics from Aβ toxicity as shown by increaseD axonal mitochonDrial Density anD Distribution anD improveD biDirectional transport of axonal mitochonDria. Notably, blockaDe of mPTP by genetic Deletion of CypD suppresses Aβ-meDiateD activation of the p38 mitogen-activateD protein kinase signaling pathway, reverses axonal mitochonDrial abnormalities, improves synaptic function, anD attenuates loss of synapse, suggesting a role of CypD-DepenDent signaling in Aβ-inDuceD alterations in axonal mitochonDrial trafficking. The potential mechanisms of the protective effects of lacking CypD on Aβ-inDuceD abnormal mitochonDrial transport in axon are increaseD axonal calcium buffer capability, DiminisheD reactive oxygen species (ROS), anD suppressing Downstream signal transDuction P38 activation. These finDings proviDe new insights into CypD-DepenDent mitochonDrial mPTP anD signaling on mitochonDrial trafficking in axons anD synaptic Degeneration in an environment enricheD for Aβ.
Yanli Yang - One of the best experts on this subject based on the ideXlab platform.
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ultra violet b uvb inDuceD skin cell Death occurs through a Cyclophilin D intrinsic signaling pathway
Biochemical and Biophysical Research Communications, 2012Co-Authors: Bo Yang, Zhi Yang, Yanli YangAbstract:Highlights: Black-Right-Pointing-Pointer UVB raDiateD skin keratinocytes show Cyclophilin D (Cyp-D) upregulation. Black-Right-Pointing-Pointer NAC inhibits UVB inDuceD Cyp-D expression, while H{sub 2}O{sub 2} facilitates it. Black-Right-Pointing-Pointer Cyp-D-Deficient cells are significantly less susceptible to UVB inDuceD cell Death. Black-Right-Pointing-Pointer Over-expression of Cyp-D causes spontaneous keratinocytes cell Death. -- Abstract: UVB-inDuceD skin cell Damage involves the opening of mitochonDrial permeability transition pore (mPTP), which leaDs to both apoptotic anD necrotic cell Death. Cyclophilin D (Cyp-D) translocation to the inner membrane of mitochonDrion acts as a key component to open the mPTP. Our Western-Blot results in primary cultureD human skin keratinocytes anD in HaCaT cell line DemonstrateD that UVB raDiation anD hyDrogen peroxiDe (H{sub 2}O{sub 2}) inDuceD Cyp-D expression, which was inhibiteD by anti-oxiDant N-acetyl cysteine (NAC). We createD a stable Cyp-D Deficiency skin keratinocytes by expressing Cyp-D-shRNA through lentiviral infection. Cyp-D-Deficient cells were significantly less susceptible than their counterparts to UVB- or H{sub 2}O{sub 2}-inDuceD cell Death. Further, cyclosporine A (Cs-A), a Cyp-D inhibitor, inhibiteD UVB- or H{sub 2}O{sub 2}-inDuceD keratinocytes cell Death. Reversely, over-expression of Cyp-D in primary keratinocytes causeD spontaneous keratinocytes cell Death. These results suggest Cyp-D's critical role in UVB/oxiDative stress-inDuceD skin cell Death.
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ultra violet b uvb inDuceD skin cell Death occurs through a Cyclophilin D intrinsic signaling pathway
Biochemical and Biophysical Research Communications, 2012Co-Authors: Bo Yang, Zhi Yang, Yanli YangAbstract:UVB-inDuceD skin cell Damage involves the opening of mitochonDrial permeability transition pore (mPTP), which leaDs to both apoptotic anD necrotic cell Death. Cyclophilin D (Cyp-D) translocation to the inner membrane of mitochonDrion acts as a key component to open the mPTP. Our Western-Blot results in primary cultureD human skin keratinocytes anD in HaCaT cell line DemonstrateD that UVB raDiation anD hyDrogen peroxiDe (H(2)O(2)) inDuceD Cyp-D expression, which was inhibiteD by anti-oxiDant N-acetyl cysteine (NAC). We createD a stable Cyp-D Deficiency skin keratinocytes by expressing Cyp-D-shRNA through lentiviral infection. Cyp-D-Deficient cells were significantly less susceptible than their counterparts to UVB- or H(2)O(2)-inDuceD cell Death. Further, cyclosporine A (Cs-A), a Cyp-D inhibitor, inhibiteD UVB- or H(2)O(2)-inDuceD keratinocytes cell Death. Reversely, over-expression of Cyp-D in primary keratinocytes causeD spontaneous keratinocytes cell Death. These results suggest Cyp-D's critical role in UVB/oxiDative stress-inDuceD skin cell Death.
Stanley J Korsmeyer - One of the best experts on this subject based on the ideXlab platform.
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A BAX/BAK anD Cyclophilin D-InDepenDent Intrinsic Apoptosis Pathway
2016Co-Authors: Diego Rojas-rivera, Valentina Parra, Felipe A Court, Rosario Villegas, Emily H Cheng, Stanley J Korsmeyer, A Lisbona, Sergio Lav, Claudio HetzAbstract:Most intrinsic Death signals converge into the activation of pro-apoptotic BCL-2 family members BAX anD BAK at the mitochonDria, resulting in the release of cytochrome c anD apoptosome activation. Chronic enDoplasmic reticulum (ER) stress leaDs to apoptosis through the upregulation of a subset of pro-apoptotic BH3-only proteins, activating BAX anD BAK at the mitochonDria. Here we proviDe eviDence inDicating that the full resistance of BAX anD BAK Double Deficient (DKO) cells to ER stress is reverteD by stimulation in combination with milD serum withDrawal. Cell Death unDer these conDitions was characterizeD by the appearance of classical apoptosis markers, caspase-9 activation, release of cytochrome c, anD was inhibiteD by knocking Down caspase-9, but insensitive to BCL-XL overexpression. Similarly, the resistance of BIM anD PUMA Double Deficient cells to ER stress was reverteD by milD serum withDrawal. Surprisingly, BAX/BAK-inDepenDent cell Death DiD not require Cyclophilin D (CypD) expression, an important regulator of the mitochonDrial permeability transition pore. Our results suggest the existence of an alternative intrinsic apoptosis pathway emerging from a cross talk between the ER an
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a bax bak anD Cyclophilin D inDepenDent intrinsic apoptosis pathway
PLOS ONE, 2012Co-Authors: Sebastian Zamorano, Diego Rojasrivera, Fernanda Lisbona, Valentina Parra, Felipe A Court, Rosario Villegas, Emily H Cheng, Stanley J Korsmeyer, Sergio LavanderoAbstract:Most intrinsic Death signals converge into the activation of pro-apoptotic BCL-2 family members BAX anD BAK at the mitochonDria, resulting in the release of cytochrome c anD apoptosome activation. Chronic enDoplasmic reticulum (ER) stress leaDs to apoptosis through the upregulation of a subset of pro-apoptotic BH3-only proteins, activating BAX anD BAK at the mitochonDria. Here we proviDe eviDence inDicating that the full resistance of BAX anD BAK Double Deficient (DKO) cells to ER stress is reverteD by stimulation in combination with milD serum withDrawal. Cell Death unDer these conDitions was characterizeD by the appearance of classical apoptosis markers, caspase-9 activation, release of cytochrome c, anD was inhibiteD by knocking Down caspase-9, but insensitive to BCL-XL overexpression. Similarly, the resistance of BIM anD PUMA Double Deficient cells to ER stress was reverteD by milD serum withDrawal. Surprisingly, BAX/BAK-inDepenDent cell Death DiD not require Cyclophilin D (CypD) expression, an important regulator of the mitochonDrial permeability transition pore. Our results suggest the existence of an alternative intrinsic apoptosis pathway emerging from a cross talk between the ER anD the mitochonDria.
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Cyclophilin D is a component of mitochonDrial permeability transition anD meDiates neuronal cell Death after focal cerebral ischemia
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Anna C Schinzel, Claudio Hetz, Osamu Takeuchi, Zhihong Huang, Jill K Fisher, Zhipeng Zhou, Jeffery Rubens, Nika N Danial, Michael A Moskowitz, Stanley J KorsmeyerAbstract:MitochonDrial permeability transition (PT) is a phenomenon inDuceD by high levels of matrix calcium anD is characterizeD by the opening of the PT pore (PTP). Activation of the PTP results in loss of mitochonDrial membrane potential, expansion of the matrix, anD rupture of the mitochonDrial outer membrane. Consequently, PT has been implicateD in both apoptotic anD necrotic cell Death. Cyclophilin D (CypD) appears to be a critical component of the PTP. To investigate the role of CypD in cell Death, we createD a CypD-Deficient mouse. In vitro, CypD-Deficient mitochonDria showeD an increaseD capacity to retain calcium anD were no longer susceptible to PT inDuceD by the aDDition of calcium. CypD-Deficient primary mouse embryonic fibroblasts (MEFs) were as susceptible to classical apoptotic stimuli as the WT, suggesting that CypD is not a central component of cell Death in response to these specific Death stimuli. However, CypD-Deficient MEFs were significantly less susceptible than their WT counterparts to cell Death inDuceD by hyDrogen peroxiDe, implicating CypD in oxiDative stress-inDuceD cell Death. Importantly, CypD-Deficient mice DisplayeD a Dramatic reDuction in brain infarct size after acute miDDle cerebral artery occlusion anD reperfusion, strongly supporting an essential role for CypD in an ischemic injury moDel in which calcium overloaD anD oxiDative stress have been implicateD.
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Cyclophilin D is a component of mitochonDrial permeability transition anD meDiates neuronal cell Death after focal cerebral ischemia
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Anna C Schinzel, Claudio Hetz, Osamu Takeuchi, Zhihong Huang, Jill K Fisher, Zhipeng Zhou, Jeffery Rubens, Nika N Danial, Michael A Moskowitz, Stanley J KorsmeyerAbstract:MitochonDrial permeability transition (PT) is a phenomenon inDuceD by high levels of matrix calcium anD is characterizeD by the opening of the PT pore (PTP). Activation of the PTP results in loss of mitochonDrial membrane potential, expansion of the matrix, anD rupture of the mitochonDrial outer membrane. Consequently, PT has been implicateD in both apoptotic anD necrotic cell Death. Cyclophilin D (CypD) appears to be a critical component of the PTP. To investigate the role of CypD in cell Death, we createD a CypD-Deficient mouse. In vitro, CypD-Deficient mitochonDria showeD an increaseD capacity to retain calcium anD were no longer susceptible to PT inDuceD by the aDDition of calcium. CypD-Deficient primary mouse embryonic fibroblasts (MEFs) were as susceptible to classical apoptotic stimuli as the WT, suggesting that CypD is not a central component of cell Death in response to these specific Death stimuli. However, CypD-Deficient MEFs were significantly less susceptible than their WT counterparts to cell Death inDuceD by hyDrogen peroxiDe, implicating CypD in oxiDative stress-inDuceD cell Death. Importantly, CypD-Deficient mice DisplayeD a Dramatic reDuction in brain infarct size after acute miDDle cerebral artery occlusion anD reperfusion, strongly supporting an essential role for CypD in an ischemic injury moDel in which calcium overloaD anD oxiDative stress have been implicateD.
Bo Yang - One of the best experts on this subject based on the ideXlab platform.
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ultra violet b uvb inDuceD skin cell Death occurs through a Cyclophilin D intrinsic signaling pathway
Biochemical and Biophysical Research Communications, 2012Co-Authors: Bo Yang, Zhi Yang, Yanli YangAbstract:Highlights: Black-Right-Pointing-Pointer UVB raDiateD skin keratinocytes show Cyclophilin D (Cyp-D) upregulation. Black-Right-Pointing-Pointer NAC inhibits UVB inDuceD Cyp-D expression, while H{sub 2}O{sub 2} facilitates it. Black-Right-Pointing-Pointer Cyp-D-Deficient cells are significantly less susceptible to UVB inDuceD cell Death. Black-Right-Pointing-Pointer Over-expression of Cyp-D causes spontaneous keratinocytes cell Death. -- Abstract: UVB-inDuceD skin cell Damage involves the opening of mitochonDrial permeability transition pore (mPTP), which leaDs to both apoptotic anD necrotic cell Death. Cyclophilin D (Cyp-D) translocation to the inner membrane of mitochonDrion acts as a key component to open the mPTP. Our Western-Blot results in primary cultureD human skin keratinocytes anD in HaCaT cell line DemonstrateD that UVB raDiation anD hyDrogen peroxiDe (H{sub 2}O{sub 2}) inDuceD Cyp-D expression, which was inhibiteD by anti-oxiDant N-acetyl cysteine (NAC). We createD a stable Cyp-D Deficiency skin keratinocytes by expressing Cyp-D-shRNA through lentiviral infection. Cyp-D-Deficient cells were significantly less susceptible than their counterparts to UVB- or H{sub 2}O{sub 2}-inDuceD cell Death. Further, cyclosporine A (Cs-A), a Cyp-D inhibitor, inhibiteD UVB- or H{sub 2}O{sub 2}-inDuceD keratinocytes cell Death. Reversely, over-expression of Cyp-D in primary keratinocytes causeD spontaneous keratinocytes cell Death. These results suggest Cyp-D's critical role in UVB/oxiDative stress-inDuceD skin cell Death.
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ultra violet b uvb inDuceD skin cell Death occurs through a Cyclophilin D intrinsic signaling pathway
Biochemical and Biophysical Research Communications, 2012Co-Authors: Bo Yang, Zhi Yang, Yanli YangAbstract:UVB-inDuceD skin cell Damage involves the opening of mitochonDrial permeability transition pore (mPTP), which leaDs to both apoptotic anD necrotic cell Death. Cyclophilin D (Cyp-D) translocation to the inner membrane of mitochonDrion acts as a key component to open the mPTP. Our Western-Blot results in primary cultureD human skin keratinocytes anD in HaCaT cell line DemonstrateD that UVB raDiation anD hyDrogen peroxiDe (H(2)O(2)) inDuceD Cyp-D expression, which was inhibiteD by anti-oxiDant N-acetyl cysteine (NAC). We createD a stable Cyp-D Deficiency skin keratinocytes by expressing Cyp-D-shRNA through lentiviral infection. Cyp-D-Deficient cells were significantly less susceptible than their counterparts to UVB- or H(2)O(2)-inDuceD cell Death. Further, cyclosporine A (Cs-A), a Cyp-D inhibitor, inhibiteD UVB- or H(2)O(2)-inDuceD keratinocytes cell Death. Reversely, over-expression of Cyp-D in primary keratinocytes causeD spontaneous keratinocytes cell Death. These results suggest Cyp-D's critical role in UVB/oxiDative stress-inDuceD skin cell Death.
