AMPK Activation Prevents and Reverses Drug-Induced Mitochondrial and Hepatocyte Injury by Promoting Mitochondrial Fusion and Function.
AMPK Activation Prevents and Reverses Drug-Induced Mitochondrial and Hepatocyte Injury by Promoting Mitochondrial Fusion and Function.
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DOI：
10.1371/journal.pone.0165638
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Fu D
中科院分区：
文献类型：
--
作者：
Kang SW;Haydar G;Taniane C;Farrell G;Arias IM;Lippincott-Schwartz J;Fu D
线粒体损伤是药物性肝病的主要潜在因素，但阻碍线粒体损伤的条件是否能预防或逆转药物性肝损伤尚不清楚。调节线粒体质量控制的一个关键分子是腺苷酸活化激酶（AMPK）。当被激活时，AMPK使线粒体伸长/融合和增殖，此时线粒体产生更多的三磷酸腺苷（ATP）且活性氧物质减少。自噬也被触发，这是一个能够清除受损/有缺陷线粒体的过程。为了探究AMPK激活是否可能预防或逆转药物诱导的线粒体和肝细胞损伤的影响，我们将一种AMPK激活剂添加到暴露于肝毒性药物对乙酰氨基酚或双氯芬酸的大鼠和人肝细胞的胶原三明治培养物中。在没有AMPK激活的情况下，这些药物导致肝细胞失去极化形态，ATP水平和活力显著降低。在亚细胞水平，由于线粒体融合蛋白Mfn1、Mfn2和/或Opa1表达降低，线粒体发生碎片化且膜电位降低。在药物暴露时添加AICAR（一种特异性AMPK激活剂）可预防并逆转这些影响。线粒体高度融合，ATP产生增加，肝细胞保持极化形态。在探究这种预防和逆转作用的机制时，我们发现AMPK激活阻止了药物介导的Mfn1、Mfn2和Opa1的降低。AMPK激活还刺激了自噬/线粒体自噬，在对乙酰氨基酚处理的细胞中最为显著。这些结果表明，AMPK的激活通过调节线粒体融合和自噬来预防/逆转药物诱导的线粒体和肝细胞损伤，使其成为治疗药物性肝损伤的一种潜在有价值的方法。
Mitochondrial damage is the major factor underlying drug-induced liver disease but whether conditions that thwart mitochondrial injury can prevent or reverse drug-induced liver damage is unclear. A key molecule regulating mitochondria quality control is AMP activated kinase (AMPK). When activated, AMPK causes mitochondria to elongate/fuse and proliferate, with mitochondria now producing more ATP and less reactive oxygen species. Autophagy is also triggered, a process capable of removing damaged/defective mitochondria. To explore whether AMPK activation could potentially prevent or reverse the effects of drug-induced mitochondrial and hepatocellular damage, we added an AMPK activator to collagen sandwich cultures of rat and human hepatocytes exposed to the hepatotoxic drugs, acetaminophen or diclofenac. In the absence of AMPK activation, the drugs caused hepatocytes to lose polarized morphology and have significantly decreased ATP levels and viability. At the subcellular level, mitochondria underwent fragmentation and had decreased membrane potential due to decreased expression of the mitochondrial fusion proteins Mfn1, 2 and/or Opa1. Adding AICAR, a specific AMPK activator, at the time of drug exposure prevented and reversed these effects. The mitochondria became highly fused and ATP production increased, and hepatocytes maintained polarized morphology. In exploring the mechanism responsible for this preventive and reversal effect, we found that AMPK activation prevented drug-mediated decreases in Mfn1, 2 and Opa1. AMPK activation also stimulated autophagy/mitophagy, most significantly in acetaminophen-treated cells. These results suggest that activation of AMPK prevents/reverses drug-induced mitochondrial and hepatocellular damage through regulation of mitochondrial fusion and autophagy, making it a potentially valuable approach for treatment of drug-induced liver injury.
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DOI：
10.1186/cc1475
发表时间：
2002-04
期刊：
Critical care (London, England)
影响因子：
--
作者：
Gyamlani GG;Parikh CR
通讯作者：
Parikh CR
影响因子：
3.8
作者：
Jaeschke, H;Gores, GJ;Lemasters, JJ
通讯作者：
Lemasters, JJ
影响因子：
3.2
作者：
Jemnitz, Katalin;Veres, Zsuzsa;Vereczkey, Laszlo
通讯作者：
Vereczkey, Laszlo
DOI：
10.1073/pnas.0705070104
发表时间：
2007-07-17
影响因子：
11.1
作者：
Jaeger, Sibylle;Handschin, Christoph;Spiegelman, Bruce M.
通讯作者：
Spiegelman, Bruce M.
影响因子：
4.4
作者：
Cantó C;Auwerx J
通讯作者：
Auwerx J