Exercise mitigates mitochondrial permeability transition pore and quality control mechanisms alterations in nonalcoholic steatohepatitis
Exercise mitigates mitochondrial permeability transition pore and quality control mechanisms alterations in nonalcoholic steatohepatitis
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DOI：
10.1139/apnm-2015-0470
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发表时间：
2016-03-01
影响因子：
3.4
通讯作者：
Magalhaes, Jose
中科院分区：
文献类型：
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作者：
Goncalves, Ines O.;Passos, Emanuel;Magalhaes, Jose
线粒体质量控制和细胞凋亡已被描述为非酒精性脂肪性肝炎（NASH）发病机制中的关键组成部分;运动被认为是抵消NASH相关后果的非药物策略。我们的目的是分析自愿体力活动（VPA）和耐力训练（ET）对NASH诱导的线粒体通透性转换孔（mPTP）开放和线粒体和细胞质量控制有害改变的影响。将48只雄性Sprague-Dawley大鼠分为标准饮食久坐组（SS，n = 16）、标准饮食VPA组（n = 8）、高脂饮食久坐组（HS，n = 16）和高脂饮食VPA组（n = 8）。饮食治疗9周后，SS组和HS组中的一半参与ET程序，8周，5天/周，1小时。通过渗透性肿胀、mPTP相关蛋白的肝脏mPTP易感性（亲环素D、Sirtuin 3、Cofilin-1），线粒体生物发生的标志物（（线粒体转录因子A（Tfam）和过氧化物酶体增殖物激活受体γ共激活蛋白（PGC-1a）），动力学（线粒体融合蛋白I（Mfnl）、线粒体融合蛋白2（Mfn 2）、动力蛋白相关蛋白1和视神经萎缩1）），自体/线粒体自噬评估了Beclin-1、微管相关蛋白1轻链3、p62、PINK 1和Parkin）、凋亡信号传导（Bax、Bcl-2）和半胱天冬酶样活性。HS动物显示出对mPTP的敏感性增加，Tfam、Mfnl、PINKl和Parkin的表达受损以及Bax含量增加（HS相对于SS）。ET和VPA改善了生物发生相关蛋白（PGC-1a）和自噬信号（Beclin-1和Beclin-1/Bc 1 -2比值），降低了凋亡信号（caspase 8活性、Bax含量和Bax/Bc 1 -2比值）。然而，只有ET降低mPTP的敏感性，并正调节Bcl-2，Tfam，Mfii 1，Mfii 2，PINK 1和Parkin含量。总之，运动降低了对NASH诱导的inPTP的易感性增加，并促进了自噬/线粒体自噬和线粒体融合向保护性表型的增加。
Mitochondrial quality control and apoptosis have been described as key components in the pathogenesis of nonalcoholic steatohepatitis (NASH); exercise is recognized as a nonpharmacological strategy to counteract NASH-associated consequences. We aimed to analyze the effect of voluntary physical activity (VPA) and endurance training (ET) against NASH-induced mitochondrial permeability transition pore (mPTP) opening and mitochondrial and cellular quality control deleterious alterations. Forty-eight male Sprague-Dawley rats were divided into standard -diet sedentary (SS, n = 16), standard -diet VPA (n = 8), high-fat diet sedentary (HS, n = 16), and high -fat diet VPA(n = 8). After 9 weeks of diet treatment, half of the SS and HS groups were engaged in an ET program for 8 weeks, 5 days/week, 1 hfclay. Liver mPTP susceptibility through osmotic swelling, mPTP-related proteins (cyclophilin D, Sirtuin3, Cofilin-1), markers of mitochondrial biogenesis ((mitochondrial transcription factor A (Tfam) and peroxisome proliferator-activated receptor gamma co-activator protein (PGC-1a)), dynamics (Mitofusin I (Mfnl), Mitofusin 2 (Mfn2), Dynamin related protein 1, and Optic atrophy 1)), auto/mitophagy (Beclin-1, microtubule-associated protein 1 light chain 3, p62, PINK1, and Parkin), and apoptotic signaling (Bax, Bcl-2) and caspases-like activities were assessed. HS animals showed an increased susceptibility to mPTP, compromised expression of Tfam, Mfnl, PINK1, and Parkin and an increase in Bax content (HS vs. SS). ET and VPA improved biogenesis -related proteins (PGC-1a) and autophagy signaling (Beclin-1 and Beclin-1/Bc1-2 ratio) and decreased apoptotic signaling (caspases 8 activity, Bax content, and Bax/Bc1-2 ratio). However, only ET decreased mPTP susceptibility and positively modulated Bcl-2, Tfam, Mfiul, Mfii2, PINK1, and Parkin content. In conclusion, exercise reduces the increased susceptibility to inPTP induced by NASH and promotes the increase of auto/mitophagy and mitochondrial fusion towards a protective phenotype.