Kathryn Taggart, Amara Estrada, Patrick Thompson, Francisco Lourenco, Sara Kirmani, Silveli Suzuki-Hatano, Christina A Pacak
{"title":"PDK4缺乏诱导扩张型心肌病杜宾犬成纤维细胞对饥饿的内在凋亡","authors":"Kathryn Taggart, Amara Estrada, Patrick Thompson, Francisco Lourenco, Sara Kirmani, Silveli Suzuki-Hatano, Christina A Pacak","doi":"10.1089/biores.2017.0023","DOIUrl":null,"url":null,"abstract":"<p><p>The Doberman pinscher (DP) canine breed displays a high incidence of idiopathic, nonischemic dilated cardiomyopathy (DCM) with increased mortality. A common mutation in DPs is a splice site deletion in the pyruvate dehydrogenase kinase 4 (PDK4) gene that shows a positive correlation with DCM development. PDK4, a vital mitochondrial protein, controls the switch between glycolysis and oxidative phosphorylation based upon nutrient availability. It is likely, although unproven, that DPs with the PDK4 mutation are unable to switch to oxidative phosphorylation during periods of low nutrient availability, and thus are highly susceptible to mitochondrial-mediated apoptosis. This study investigated cell viability, mitochondrial stress, and activation of the intrinsic (mitochondrial mediated) apoptotic pathway in dermal fibroblasts from DPs that were healthy (PDK4<sup>wt/wt</sup>), heterozygous (PDK4<sup>wt/del</sup>), and homozygous (PDK4<sup>del/del</sup>) for the PDK4 mutation under conditions of high (unstarved) and low (starved) nutrient availability <i>in vitro</i>. As hypothesized, PDK4<sup>wt/del</sup> and PDK4<sup>del/del</sup> cells showed evidence of mitochondrial stress and activation of the intrinsic apoptotic pathway following starvation, while the PDK4<sup>wt/wt</sup> cells remained healthy and viable under these conditions. Adeno-associated virus (AAV) PDK4-mediated gene replacement experiments confirmed cause-effect relationships between PDK4 deficiency and apoptosis activation. The restoration of function observed following administration of AAV-PDK4 provides strong support for the translation of this gene therapy approach into the clinical realm for PDK4-affected Dobermans.</p>","PeriodicalId":9100,"journal":{"name":"BioResearch Open Access","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/biores.2017.0023","citationCount":"11","resultStr":"{\"title\":\"PDK4 Deficiency Induces Intrinsic Apoptosis in Response to Starvation in Fibroblasts from Doberman Pinschers with Dilated Cardiomyopathy.\",\"authors\":\"Kathryn Taggart, Amara Estrada, Patrick Thompson, Francisco Lourenco, Sara Kirmani, Silveli Suzuki-Hatano, Christina A Pacak\",\"doi\":\"10.1089/biores.2017.0023\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The Doberman pinscher (DP) canine breed displays a high incidence of idiopathic, nonischemic dilated cardiomyopathy (DCM) with increased mortality. A common mutation in DPs is a splice site deletion in the pyruvate dehydrogenase kinase 4 (PDK4) gene that shows a positive correlation with DCM development. PDK4, a vital mitochondrial protein, controls the switch between glycolysis and oxidative phosphorylation based upon nutrient availability. It is likely, although unproven, that DPs with the PDK4 mutation are unable to switch to oxidative phosphorylation during periods of low nutrient availability, and thus are highly susceptible to mitochondrial-mediated apoptosis. This study investigated cell viability, mitochondrial stress, and activation of the intrinsic (mitochondrial mediated) apoptotic pathway in dermal fibroblasts from DPs that were healthy (PDK4<sup>wt/wt</sup>), heterozygous (PDK4<sup>wt/del</sup>), and homozygous (PDK4<sup>del/del</sup>) for the PDK4 mutation under conditions of high (unstarved) and low (starved) nutrient availability <i>in vitro</i>. As hypothesized, PDK4<sup>wt/del</sup> and PDK4<sup>del/del</sup> cells showed evidence of mitochondrial stress and activation of the intrinsic apoptotic pathway following starvation, while the PDK4<sup>wt/wt</sup> cells remained healthy and viable under these conditions. Adeno-associated virus (AAV) PDK4-mediated gene replacement experiments confirmed cause-effect relationships between PDK4 deficiency and apoptosis activation. The restoration of function observed following administration of AAV-PDK4 provides strong support for the translation of this gene therapy approach into the clinical realm for PDK4-affected Dobermans.</p>\",\"PeriodicalId\":9100,\"journal\":{\"name\":\"BioResearch Open Access\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2017-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1089/biores.2017.0023\",\"citationCount\":\"11\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"BioResearch Open Access\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1089/biores.2017.0023\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2017/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"Biochemistry, Genetics and Molecular Biology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"BioResearch Open Access","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1089/biores.2017.0023","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2017/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
PDK4 Deficiency Induces Intrinsic Apoptosis in Response to Starvation in Fibroblasts from Doberman Pinschers with Dilated Cardiomyopathy.
The Doberman pinscher (DP) canine breed displays a high incidence of idiopathic, nonischemic dilated cardiomyopathy (DCM) with increased mortality. A common mutation in DPs is a splice site deletion in the pyruvate dehydrogenase kinase 4 (PDK4) gene that shows a positive correlation with DCM development. PDK4, a vital mitochondrial protein, controls the switch between glycolysis and oxidative phosphorylation based upon nutrient availability. It is likely, although unproven, that DPs with the PDK4 mutation are unable to switch to oxidative phosphorylation during periods of low nutrient availability, and thus are highly susceptible to mitochondrial-mediated apoptosis. This study investigated cell viability, mitochondrial stress, and activation of the intrinsic (mitochondrial mediated) apoptotic pathway in dermal fibroblasts from DPs that were healthy (PDK4wt/wt), heterozygous (PDK4wt/del), and homozygous (PDK4del/del) for the PDK4 mutation under conditions of high (unstarved) and low (starved) nutrient availability in vitro. As hypothesized, PDK4wt/del and PDK4del/del cells showed evidence of mitochondrial stress and activation of the intrinsic apoptotic pathway following starvation, while the PDK4wt/wt cells remained healthy and viable under these conditions. Adeno-associated virus (AAV) PDK4-mediated gene replacement experiments confirmed cause-effect relationships between PDK4 deficiency and apoptosis activation. The restoration of function observed following administration of AAV-PDK4 provides strong support for the translation of this gene therapy approach into the clinical realm for PDK4-affected Dobermans.
BioResearch Open AccessBiochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
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1
期刊介绍:
BioResearch Open Access is a high-quality open access journal providing peer-reviewed research on a broad range of scientific topics, including molecular and cellular biology, tissue engineering, regenerative medicine, stem cells, gene therapy, systems biology, genetics, virology, and neuroscience. The Journal publishes basic science and translational research in the form of original research articles, comprehensive review articles, mini-reviews, rapid communications, brief reports, technology reports, hypothesis articles, perspectives, and letters to the editor.