Jun Tao, Junxiong Qiu, Junmeng Zheng, Ruibing Li, Xing Chang, Qingyong He
{"title":"磷酸甘油酸突变酶 5 通过诱导 prohibitin-2 去磷酸化和损害线粒体质量控制，加剧雄性小鼠的酒精性心肌病。","authors":"Jun Tao, Junxiong Qiu, Junmeng Zheng, Ruibing Li, Xing Chang, Qingyong He","doi":"10.1002/ctm2.1806","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>The induction of mitochondrial quality control (MQC) mechanisms is essential for the re-establishment of mitochondrial homeostasis and cellular bioenergetics during periods of stress. Although MQC activation has cardioprotective effects in various cardiovascular diseases, its precise role and regulatory mechanisms in alcoholic cardiomyopathy (ACM) remain incompletely understood.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We explored whether two mitochondria-related proteins, phosphoglycerate mutase 5 (Pgam5) and prohibitin 2 (Phb2), influence MQC in male mice during ACM.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Myocardial Pgam5 expression was upregulated in a male mouse model of ACM. Notably, following ACM induction, heart dysfunction was markedly reversed in male cardiomyocyte-specific <i>Pgam5</i> knockout (<i>Pgam5<sup>cKO</sup></i>) mice. Meanwhile, in alcohol-treated male mouse-derived neonatal cardiomyocytes, <i>Pgam5</i> depletion preserved cell survival and restored mitochondrial dynamics, mitophagy, mitochondrial biogenesis and the mitochondrial unfolded protein response (mtUPR). We further found that in alcohol-treated cardiomyocyte, Pgam5 binds Phb2 and induces its dephosphorylation at Ser91. Alternative transduction of phospho-mimetic (Phb2<sup>S91D</sup>) and phospho-defective (Phb2<sup>S9A</sup>) Phb2 mutants attenuated and enhanced, respectively, alcohol-related mitochondrial dysfunction in cardiomyocytes. Moreover, transgenic male mice expressing <i>Phb2<sup>S91D</sup></i> were resistant to alcohol-induced heart dysfunction.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>We conclude that ACM-induced Pgam5 upregulation results in Pgam5-dependent Phb2<sup>S91</sup> dephosphorylation, leading to MQC destabilisation and mitochondrial dysfunction in heart. Therefore, modulating the Pgam5/Phb2 interaction could potentially offer a novel therapeutic strategy for ACM in male mice.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li><i>Pgam5</i> knockout attenuates alcohol-induced cardiac histopathology and heart dysfunction in male mice.</li>\n \n <li><i>Pgam5</i> KO reduces alcohol-induced myocardial inflammation, lipid peroxidation and metabolic dysfunction in male mice.</li>\n \n <li>Pgam5 depletion protects mitochondrial function in alcohol-exposed male mouse cardiomyocytes.</li>\n \n <li>Pgam5 depletion normalises MQC in ACM.</li>\n \n <li>EtOH impairs MQC through inducing Phb2 dephosphorylation at Ser91.</li>\n \n <li>Pgam5 interacts with Phb2 and induces Phb2 dephosphorylation.</li>\n \n <li>Transgenic mice expressing a Ser91 phospho-mimetic Phb2 mutant are resistant to ACM.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9000,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1806","citationCount":"0","resultStr":"{\"title\":\"Phosphoglycerate mutase 5 exacerbates alcoholic cardiomyopathy in male mice by inducing prohibitin-2 dephosphorylation and impairing mitochondrial quality control\",\"authors\":\"Jun Tao, Junxiong Qiu, Junmeng Zheng, Ruibing Li, Xing Chang, Qingyong He\",\"doi\":\"10.1002/ctm2.1806\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>The induction of mitochondrial quality control (MQC) mechanisms is essential for the re-establishment of mitochondrial homeostasis and cellular bioenergetics during periods of stress. Although MQC activation has cardioprotective effects in various cardiovascular diseases, its precise role and regulatory mechanisms in alcoholic cardiomyopathy (ACM) remain incompletely understood.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>We explored whether two mitochondria-related proteins, phosphoglycerate mutase 5 (Pgam5) and prohibitin 2 (Phb2), influence MQC in male mice during ACM.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Myocardial Pgam5 expression was upregulated in a male mouse model of ACM. Notably, following ACM induction, heart dysfunction was markedly reversed in male cardiomyocyte-specific <i>Pgam5</i> knockout (<i>Pgam5<sup>cKO</sup></i>) mice. Meanwhile, in alcohol-treated male mouse-derived neonatal cardiomyocytes, <i>Pgam5</i> depletion preserved cell survival and restored mitochondrial dynamics, mitophagy, mitochondrial biogenesis and the mitochondrial unfolded protein response (mtUPR). We further found that in alcohol-treated cardiomyocyte, Pgam5 binds Phb2 and induces its dephosphorylation at Ser91. Alternative transduction of phospho-mimetic (Phb2<sup>S91D</sup>) and phospho-defective (Phb2<sup>S9A</sup>) Phb2 mutants attenuated and enhanced, respectively, alcohol-related mitochondrial dysfunction in cardiomyocytes. Moreover, transgenic male mice expressing <i>Phb2<sup>S91D</sup></i> were resistant to alcohol-induced heart dysfunction.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>We conclude that ACM-induced Pgam5 upregulation results in Pgam5-dependent Phb2<sup>S91</sup> dephosphorylation, leading to MQC destabilisation and mitochondrial dysfunction in heart. Therefore, modulating the Pgam5/Phb2 interaction could potentially offer a novel therapeutic strategy for ACM in male mice.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Highlights</h3>\\n \\n <div>\\n <ul>\\n \\n <li><i>Pgam5</i> knockout attenuates alcohol-induced cardiac histopathology and heart dysfunction in male mice.</li>\\n \\n <li><i>Pgam5</i> KO reduces alcohol-induced myocardial inflammation, lipid peroxidation and metabolic dysfunction in male mice.</li>\\n \\n <li>Pgam5 depletion protects mitochondrial function in alcohol-exposed male mouse cardiomyocytes.</li>\\n \\n <li>Pgam5 depletion normalises MQC in ACM.</li>\\n \\n <li>EtOH impairs MQC through inducing Phb2 dephosphorylation at Ser91.</li>\\n \\n <li>Pgam5 interacts with Phb2 and induces Phb2 dephosphorylation.</li>\\n \\n <li>Transgenic mice expressing a Ser91 phospho-mimetic Phb2 mutant are resistant to ACM.</li>\\n </ul>\\n </div>\\n </section>\\n </div>\",\"PeriodicalId\":10189,\"journal\":{\"name\":\"Clinical and Translational Medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":7.9000,\"publicationDate\":\"2024-08-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1806\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical and Translational Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ctm2.1806\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ctm2.1806","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Phosphoglycerate mutase 5 exacerbates alcoholic cardiomyopathy in male mice by inducing prohibitin-2 dephosphorylation and impairing mitochondrial quality control
Background
The induction of mitochondrial quality control (MQC) mechanisms is essential for the re-establishment of mitochondrial homeostasis and cellular bioenergetics during periods of stress. Although MQC activation has cardioprotective effects in various cardiovascular diseases, its precise role and regulatory mechanisms in alcoholic cardiomyopathy (ACM) remain incompletely understood.
Methods
We explored whether two mitochondria-related proteins, phosphoglycerate mutase 5 (Pgam5) and prohibitin 2 (Phb2), influence MQC in male mice during ACM.
Results
Myocardial Pgam5 expression was upregulated in a male mouse model of ACM. Notably, following ACM induction, heart dysfunction was markedly reversed in male cardiomyocyte-specific Pgam5 knockout (Pgam5cKO) mice. Meanwhile, in alcohol-treated male mouse-derived neonatal cardiomyocytes, Pgam5 depletion preserved cell survival and restored mitochondrial dynamics, mitophagy, mitochondrial biogenesis and the mitochondrial unfolded protein response (mtUPR). We further found that in alcohol-treated cardiomyocyte, Pgam5 binds Phb2 and induces its dephosphorylation at Ser91. Alternative transduction of phospho-mimetic (Phb2S91D) and phospho-defective (Phb2S9A) Phb2 mutants attenuated and enhanced, respectively, alcohol-related mitochondrial dysfunction in cardiomyocytes. Moreover, transgenic male mice expressing Phb2S91D were resistant to alcohol-induced heart dysfunction.
Conclusions
We conclude that ACM-induced Pgam5 upregulation results in Pgam5-dependent Phb2S91 dephosphorylation, leading to MQC destabilisation and mitochondrial dysfunction in heart. Therefore, modulating the Pgam5/Phb2 interaction could potentially offer a novel therapeutic strategy for ACM in male mice.
Highlights
Pgam5 knockout attenuates alcohol-induced cardiac histopathology and heart dysfunction in male mice.
Pgam5 KO reduces alcohol-induced myocardial inflammation, lipid peroxidation and metabolic dysfunction in male mice.
Pgam5 depletion protects mitochondrial function in alcohol-exposed male mouse cardiomyocytes.
Pgam5 depletion normalises MQC in ACM.
EtOH impairs MQC through inducing Phb2 dephosphorylation at Ser91.
Pgam5 interacts with Phb2 and induces Phb2 dephosphorylation.
Transgenic mice expressing a Ser91 phospho-mimetic Phb2 mutant are resistant to ACM.
期刊介绍：
Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.
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