Mitochondrial Protection by Hexokinase-II and Akt in the Heart

己糖激酶 II 和 Akt 对心脏的线粒体保护

基本信息

  • 批准号:
    8094522
  • 负责人:
  • 金额:
    $ 38.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-08-01 至 2014-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The protein kinase Akt provides strong survival signals in cardiomyocytes, both chronically through altered gene programming, and more acutely through mechanisms that have not been fully elucidated. This proposal examines the hypothesis that activated Akt translocates to mitochondria and provides acute cardioprotection via its ability to phosphorylate hexokinase-II (HK-II) and enhance HK-II association with and inhibition of permeability transition pore (PT-pore) opening. Data I have generated in my published work show that Akt translocates to mitochondria upon acute activation by leukemia inhibitory factor (LIF), phosphorylates HK-II and prevents H202 and Ca2+induced PT-pore opening in neonatal rat ventricular myocytes or mitochondria isolated from adult mouse heart. Protective responses mediated by Akt are impaired by dissociation of HK-II. Aim #1 of this proposal seeks to establish a requirement for mitochondrial HK-II and its phosphorylation in Akt-mediated protection against PT-pore opening. This will be tested using loss and gain of function approaches in which mitochondrial HK-II is decreased by an HK-II dissociating peptide, and increased by adenoviral expression of WT HK-II, a mutated HK-II lacking its mitochondrial binding motif or kinase dead HK-II. The requirement for HK-II phosphorylation will be tested by using HK-II mutated to either prevent or mimic phosphorylation at its putative Akt phosphorylation site. To extend these findings to the adult heart, Aim #2 will examine regulation of mitochondrial Akt and HK-II and the phosphorylation of HK-II using Langendorff perfused heart model and in vivo. The effects of HK-II dissociation from mitochondria and of TAT-fusion HK-II and mutants into the heart will be tested for their effects on ischemia/reperfusion (I/R) damage in perfused heart in the presence or absence of IGF-1 or in vivo. In Aim #3, I will determine whether the recently discovered Akt-phosphatase, PHLPP-1, localizes to mitochondria and regulates mitochondrial Akt activity and thus mitochondrial HK-II/PT-pore opening. This will be examined by knockdown of PHLPP (using siRNA and PHLPP knock-out mice) and by increasing PHLPP-1 expression via adenoviral expression. These experiments will provide evidence for HK-II as a potential downstream target of Akt, and PHLPP as a potential regulator of Akt, and will suggest novel sites of intervention for inhibiting I/R induced mitochondria mediated cardiomyocyte cell death. PUBLIC HEALTH RELEVANCE: Cardiomyocyte death plays a crucial role in heart disease and opening of the permeability transition pore (PT-pore) in mitochondria is a major executor of cell death. The protein kinase Akt provides strong survival signals in cardiomyocytes and the mechanisms by which Akt prevents cell death have not been fully elucidated. This proposal examines the hypotheses that activated Akt translocates to mitochondria and provides acute cardioprotection via its ability to phosphorylate hexokinase-II (HK-II) and that this protective signaling is regulated by a Akt phosphatase at mitochondria.
描述(由申请人提供):蛋白激酶Akt在心肌细胞中提供了强的存活信号,既通过改变基因编程长期存在,又通过尚未完全阐明的机制更急性地存在。该提案检验了激活的Akt易位至线粒体并通过其磷酸化己糖激酶-II(HK-II)和增强HK-II与渗透性转换孔(PT-孔)开放的关联和抑制的能力提供急性心脏保护的假设。我在我发表的工作中产生的数据表明,Akt易位到线粒体急性激活白血病抑制因子(LIF),磷酸化HK-II,并防止H2 O2和Ca 2+诱导的PT孔开放新生大鼠心室肌细胞或线粒体分离成年小鼠心脏。由Akt介导的保护性应答因HK-II的解离而受损。该提案的目的#1寻求建立在Akt介导的针对PT孔开放的保护中对线粒体HK-II及其磷酸化的需要。这将使用功能丧失和获得方法进行测试,其中线粒体HK-II通过HK-II解离肽减少,并通过WT HK-II的腺病毒表达增加,WT HK-II是一种缺乏线粒体结合基序的突变HK-II或激酶死亡的HK-II。将通过使用突变的HK-II来检测HK-II磷酸化的需要,以防止或模拟其推定的Akt磷酸化位点处的磷酸化。为了将这些发现扩展到成人心脏,目标#2将使用Langendorff灌注心脏模型和体内检查线粒体Akt和HK-II的调节以及HK-II的磷酸化。将测试HK-II从线粒体解离和TAT融合HK-II和突变体进入心脏的作用,以确定它们在存在或不存在IGF-1的情况下或在体内对灌注心脏中的缺血/再灌注(I/R)损伤的作用。在目标#3中,我将确定最近发现的Akt-磷酸酶PHLPP-1是否定位于线粒体并调节线粒体Akt活性,从而调节线粒体HK-II/PT孔开放。这将通过PHLPP的敲低(使用siRNA和PHLPP敲除小鼠)和通过经由腺病毒表达增加PHLPP-1表达来检查。这些实验将为HK-II作为Akt的潜在下游靶点和PHLPP作为Akt的潜在调节剂提供证据,并将提出用于抑制I/R诱导的线粒体介导的心肌细胞死亡的新的干预位点。公共卫生关系:心肌细胞死亡在心脏病中起着至关重要的作用,线粒体中的渗透性转换孔(PT孔)的开放是细胞死亡的主要执行者。蛋白激酶Akt在心肌细胞中提供强的存活信号,Akt防止细胞死亡的机制尚未完全阐明。该提案研究了激活的Akt易位到线粒体并通过其磷酸化己糖激酶-II(HK-II)的能力提供急性心脏保护的假设,并且这种保护性信号传导由线粒体处的Akt磷酸酶调节。

项目成果

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Shigeki Miyamoto其他文献

Shigeki Miyamoto的其他文献

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{{ truncateString('Shigeki Miyamoto', 18)}}的其他基金

Hexokinase-II protects the heart against ischemia through regulation of autophagy
己糖激酶-II 通过调节自噬保护心脏免受缺血
  • 批准号:
    9130407
  • 财政年份:
    2015
  • 资助金额:
    $ 38.63万
  • 项目类别:
Mitochondrial Protection by Hexokinase-II and Akt in the Heart
己糖激酶 II 和 Akt 对心脏的线粒体保护
  • 批准号:
    8269124
  • 财政年份:
    2009
  • 资助金额:
    $ 38.63万
  • 项目类别:
Mitochondrial Protection by Hexokinase-II and Akt in the Heart
己糖激酶 II 和 Akt 对心脏的线粒体保护
  • 批准号:
    8469356
  • 财政年份:
    2009
  • 资助金额:
    $ 38.63万
  • 项目类别:
Mitochondrial Protection by Hexokinase-II and Akt in the Heart
己糖激酶 II 和 Akt 对心脏的线粒体保护
  • 批准号:
    7900315
  • 财政年份:
    2009
  • 资助金额:
    $ 38.63万
  • 项目类别:
Mitochondrial Protection by Hexokinase-II and Akt in the Heart
己糖激酶 II 和 Akt 对心脏的线粒体保护
  • 批准号:
    7699508
  • 财政年份:
    2009
  • 资助金额:
    $ 38.63万
  • 项目类别:

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