Mitochondrial depolarization, mitophagy, and mitochondrial DAMPs in ALD

ALD 中的线粒体去极化、线粒体自噬和线粒体 DAMP

基本信息

  • 批准号:
    10155373
  • 负责人:
  • 金额:
    $ 33.64万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-08-01 至 2023-04-30
  • 项目状态:
    已结题

项目摘要

Alcoholic liver disease (ALD) accounts for ~50% of deaths due to cirrhosis and ~30% of all liver-related deaths in the US. How ethanol damages the liver remains poorly understood, and therapies are lacking or unproven. Our goal is to understand the pathogenesis of ALD. We observed widespread, reversible hepatic mitochondrial depolarization (mtDepo), increased mitophagic burden and elevated serum mitochondrial DNA (mtDNA) in mice after ethanol treatment. We propose to test the novel hypothesis that ethanol metabolism induces mtDepo, which in turn stimulates mitophagy. Markedly increased mitophagic burden overwhelms the capacity of lysosomes to process autophagosomes, particularly when processing of depolarized mitochondria into mitophagosomes and then into lysosomes is compromised after chronic ethanol exposure, leading to extracellular release of damaged mitochondria, mitophagosomes and/or autolysosomes containing mitochondrial damage-associated molecular pattern (mtDAMP) molecules to cause a profibrotic inflammatory response and liver injury. In Specific Aim 1 using intravital multiphoton microscopy, we will explore if mtDepo occurs in living mice after chronic ethanol and is exacerbated by superimposed binge drinking and in an unique fibrosis-inducing ethanol/cholesterol model we developed. We will determine the relation of mtDepo to hepatic injury, inflammation and fibrosis. We will also explore if inhibition of acetaldehyde (AcAld) formation by alcohol dehydrogenase and CYP2E1 deficiency, accelerated AcAld oxidation by Alda-1, and FK506 (blocker of depolarization) decrease mtDepo and liver injury/inflammation/fibrosis after chronic ethanol. In Aim 2, we will determine the relation of mtDepo to mitophagy. Using genetic and pharmacological interventions in combination with intravital and electron microscopy and analyses of molecular indicators of mitophagic flux, we will elucidate if ethanol-induced mtDepo initiates mitophagy or if mitophagy causes mtDepo. We will determine if mitophagy/mitophagosome processing is blunted by chronic, chronic plus cholesterol and chronic plus binge ethanol and further explore if inhibition of autophagic processing exacerbates liver injury/inflammation/fibrosis after chronic ethanol. In Aim 3, we will characterize how mtDepo and compromised mitophagy/processing contribute to mtDAMP release after ethanol. We will characterize release into serum of mtDAMPs after acute ethanol and chronic, chronic plus cholesterol and chronic plus binge ethanol to determine the relationship of mtDAMP release to liver injury/inflammation/fibrosis. We will also determine how up and down-modulation of mtDepo, mitophagy and processing of mitophagosomes alters mtDAMP release after ethanol. This study will elucidate a novel link between early mitochondrial changes associated with ethanol metabolism and the later development of liver injury/inflammation/fibrosis and thus fill a critical gap in understanding ALD pathogenesis. This study should also identify new therapeutic targets of ALD and novel biomarkers for monitoring ALD severity/progression.
酒精性肝病(ALD)约占肝硬化死亡的50%,约占所有肝脏相关死亡的30%。 死亡在美国。乙醇如何损害肝脏仍然知之甚少,缺乏治疗方法, 未经证实。我们的目标是了解ALD的发病机制。我们观察到广泛的,可逆的肝 线粒体去极化(mtDepo)、线粒体吞噬负荷增加和血清线粒体DNA升高 (线粒体DNA)在乙醇处理后的小鼠。我们建议测试新的假设,乙醇代谢 诱导线粒体脱蛋白酶,进而刺激线粒体自噬。线粒体吞噬负荷显著增加 证明了溶酶体处理自噬体的能力,特别是在处理 去极化线粒体进入线粒体吞噬体,然后进入溶酶体, 慢性乙醇暴露,导致细胞外释放受损的线粒体,线粒体吞噬体 和/或含有线粒体损伤相关分子模式(mtDAMP)的自体溶酶体 分子引起促纤维化炎症反应和肝损伤。在具体目标1中, 活体多光子显微镜,我们将探讨mtDepo是否发生在慢性乙醇后的活小鼠中, 在一个独特的纤维化诱导乙醇/胆固醇模型中, 开发我们将确定mtDepo与肝损伤、炎症和纤维化的关系。我们还将 探讨乙醇脱氢酶和CYP 2 E1缺陷是否抑制乙醛(AcAld)形成, Alda-1加速AcAld氧化,FK 506(去极化阻滞剂)降低mtDepo和肝脏 慢性乙醇后的损伤/炎症/纤维化。在目标2中,我们将确定mtDepo与 线粒体自噬使用遗传和药物干预结合活体和电子 显微镜和线粒体吞噬通量的分子指标的分析,我们将阐明,如果乙醇诱导的 mtDepo启动线粒体自噬或线粒体自噬是否引起mtDepo。我们将确定线粒体自噬/线粒体自噬体 慢性、慢性加胆固醇和慢性加酗酒会使加工变钝,并进一步探讨 自噬加工的抑制加剧了慢性乙醇后的肝损伤/炎症/纤维化。在Aim中 3,我们将描述mtDepo和受损的线粒体自噬/加工如何有助于mtDAMP的释放 乙醇之后。我们将描述急性乙醇和慢性、慢性、慢性 加胆固醇和慢性加酗酒,以确定mtDAMP释放到肝脏的关系 损伤/炎症/纤维化。我们还将确定如何向上和向下调制mtDepo,线粒体自噬和 线粒体吞噬体的加工改变了乙醇后mtDAMP的释放。这项研究将阐明一个新的联系 与乙醇代谢相关的早期线粒体变化和肝脏发育的后期之间的关系 损伤/炎症/纤维化,从而填补了理解ALD发病机制的关键空白。这项研究应 还确定了ALD的新治疗靶点和用于监测ALD严重程度/进展的新生物标志物。

项目成果

期刊论文数量(0)
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会议论文数量(0)
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John J Lemasters其他文献

Ischemic preconditioning attenuates acute lung injury after partial liver transplantation
缺血预处理减轻部分肝移植后的急性肺损伤
  • DOI:
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Qinlong Liu;Hasibur Rehman;Yasodha Krishnasamy;John J Lemasters;Zhi Zhong
  • 通讯作者:
    Zhi Zhong

John J Lemasters的其他文献

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{{ truncateString('John J Lemasters', 18)}}的其他基金

Cell and Molecular Imaging Core
细胞和分子成像核心
  • 批准号:
    10460363
  • 财政年份:
    2021
  • 资助金额:
    $ 33.64万
  • 项目类别:
Mechanisms of Mitochondrial Iron Uptake: New Therapeutic Targets in Hepatotoxicity
线粒体铁摄取机制:肝毒性的新治疗靶点
  • 批准号:
    10210670
  • 财政年份:
    2021
  • 资助金额:
    $ 33.64万
  • 项目类别:
Mechanisms of Mitochondrial Iron Uptake: New Therapeutic Targets in Hepatotoxicity
线粒体铁摄取机制:肝毒性的新治疗靶点
  • 批准号:
    10349589
  • 财政年份:
    2021
  • 资助金额:
    $ 33.64万
  • 项目类别:
Cell and Molecular Imaging Core
细胞和分子成像核心
  • 批准号:
    10674964
  • 财政年份:
    2021
  • 资助金额:
    $ 33.64万
  • 项目类别:
Mechanisms of Mitochondrial Iron Uptake: New Therapeutic Targets in Hepatotoxicity
线粒体铁摄取机制:肝毒性的新治疗靶点
  • 批准号:
    10597049
  • 财政年份:
    2021
  • 资助金额:
    $ 33.64万
  • 项目类别:
Advanced Imaging Core
先进的成像核心
  • 批准号:
    10608981
  • 财政年份:
    2020
  • 资助金额:
    $ 33.64万
  • 项目类别:
Advanced Imaging Core
先进的成像核心
  • 批准号:
    10586110
  • 财政年份:
    2020
  • 资助金额:
    $ 33.64万
  • 项目类别:
Advanced Imaging Core
先进的成像核心
  • 批准号:
    10395945
  • 财政年份:
    2020
  • 资助金额:
    $ 33.64万
  • 项目类别:
Advanced Imaging Core
先进的成像核心
  • 批准号:
    10337321
  • 财政年份:
    2020
  • 资助金额:
    $ 33.64万
  • 项目类别:
Mitochondrial depolarization, mitophagy, and mitochondrial DAMPs in ALD
ALD 中的线粒体去极化、线粒体自噬和线粒体 DAMP
  • 批准号:
    9920650
  • 财政年份:
    2018
  • 资助金额:
    $ 33.64万
  • 项目类别:

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