PPARγ activation rescues mitochondrial function from inhibition of complex I and loss of PINK1
PPARγ activation rescues mitochondrial function from inhibition of complex I and loss of PINK1
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DOI：
10.1016/j.expneurol.2013.12.012
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发表时间：
2014-03-01
影响因子：
5.3
通讯作者：
Duchen, Michael R.
中科院分区：
文献类型：
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作者：
Carlos Corona, Juan;Campos de Souza, Senio;Duchen, Michael R.
帕金森病长期以来一直与线粒体复合物I活性受损有关，而与家族性帕金森病相关的几种基因缺陷涉及线粒体功能或“质量控制”途径的缺陷，导致线粒体生物发生和通过自噬去除功能障碍的线粒体之间的不平衡。其中包括PTEN诱导的激酶1（PINK 1）基因突变，其中线粒体功能异常。过氧化物酶体增殖物激活受体γ（PPAR γ），一种核受体和配体依赖性转录因子，调节炎症、脂质和碳水化合物代谢、抗氧化防御和线粒体生物发生的途径。我们已经发现，复合物I抑制剂鱼藤酮抑制人分化的SHSY-5 Y细胞中的复合物I不可逆地降低线粒体质量、膜电位和氧消耗，同时增加自由基产生和自噬。在PINK 1敲除细胞中也观察到类似的变化，其中电位、耗氧量和线粒体质量都降低。在这两种模型中，所有这些变化都通过用PPAR γ激动剂罗格列酮预处理细胞来逆转，罗格列酮增加线粒体生物合成，增加氧消耗并抑制自由基生成和自噬。因此，罗格列酮通过直接影响线粒体功能，在与帕金森病相关的线粒体功能障碍的两种不同模型中具有神经保护作用。(C)2013 Elsevier Inc. All rights reserved.
Parkinson's disease has long been associated with impaired mitochondrial complex I activity, while several gene defects associated with familial Parkinson's involve defects in mitochondrial function or 'quality control' pathways, causing an imbalance between mitochondrial biogenesis and removal of dysfunctional mitochondria by autophagy. Amongst these are mutations of the gene for PTEN-induced kinase 1 (PINK1) in which mitochondrial function is abnormal. Peroxisome proliferator-activated receptor gamma (PPAR gamma), a nuclear receptor and ligand-dependent transcription factor, regulates pathways of inflammation, lipid and carbohydrate metabolism, antioxidant defences and mitochondrial biogenesis. We have found that inhibition of complex I in human differentiated SHSY-5Y cells by the complex I inhibitor rotenone irreversibly decrease mitochondrial mass, membrane potential and oxygen consumption, while increasing free radical generation and autophagy. Similar changes are seen in PINK1 knockdown cells, in which potential, oxygen consumption and mitochondrial mass are all decreased. In both models, all these changes were reversed by pre-treatment of the cells with the PPAR gamma agonist, rosiglitazone, which increased mitochondrial biogenesis, increased oxygen consumption and suppressed free radical generation and autophagy. Thus, rosiglitazone is neuroprotective in two different models of mitochondrial dysfunction associated with Parkinson's disease through a direct impact on mitochondrial function. (C) 2013 Elsevier Inc. All rights reserved.