由PGC-1α促进的线粒体质量控制，在西方饮食诱导的肥胖中失调，并在小鼠适度体育活动后部分恢复。

Mitochondrial quality control, promoted by PGC-1α, is dysregulated by Western diet-induced obesity and partially restored by moderate physical activity in mice.

作者信息

Greene Nicholas P, Lee David E, Brown Jacob L, Rosa Megan E, Brown Lemuel A, Perry Richard A, Henry Jordyn N, Washington Tyrone A

机构信息

Integrative Muscle Metabolism Laboratory, Human Performance Laboratory, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, Arkansas

Integrative Muscle Metabolism Laboratory, Human Performance Laboratory, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, Arkansas.

出版信息

Physiol Rep. 2015 Jul;3(7). doi: 10.14814/phy2.12470.

Skeletal muscle mitochondrial degeneration is a hallmark of insulin resistance/obesity marked by lost function, enhanced ROS emission, and altered morphology which may be ameliorated by physical activity (PA). However, no prior report has examined mitochondrial quality control regulation throughout biogenesis, fusion/fission dynamics, autophagy, and mitochondrial permeability transition pore (MPTP) in obesity. Therefore, we determined how each process is impacted by Western diet (WD)-induced obesity and whether voluntary PA may alleviate derangements in mitochondrial quality control mechanisms. Despite greater mitochondrial content following WD (COX-IV and Cytochrome C), induction of biogenesis controllers appears impaired (failed induction of PGC-1α). Mitochondrial fusion seems diminished (reduced MFN2, Opa1 proteins), with no significant changes in fission, suggesting a shift in balance of dynamics regulation favoring fission. Autophagy flux was promoted in WD (reduced p62, increased LC3II:I ratio); however, mitophagy marker BNIP3 is reduced in WD which may indicate reduced mitophagy despite enhanced total autophagy flux. MPTP regulator Ant mRNA is reduced by WD. Few processes were impacted by physical activity. Finally, mitochondrial quality control processes are partially promoted by PGC-1α, as PGC-1α transgenic mice display elevated mitochondrial biogenesis and autophagy flux. Additionally, these mice exhibit elevated Mfn1 and Opa1 mRNA, with no change in protein content suggesting these factors are transcriptionally promoted by PGC-1α overexpression. These data demonstrate dysfunctions across mitochondrial quality control in obesity and that PGC-1α is sufficient to promote multiple, but not necessarily all, aspects of mitochondrial quality control. Mitochondrial quality control may therefore be an opportune target to therapeutically treat metabolic disease.

骨骼肌线粒体退化是胰岛素抵抗/肥胖的一个标志，其特征是功能丧失、活性氧（ROS）释放增加以及形态改变，而体育活动（PA）可能会改善这些情况。然而，之前没有报告研究过肥胖状态下线粒体在整个生物发生、融合/分裂动态、自噬以及线粒体通透性转换孔（MPTP）方面的质量控制调节。因此，我们确定了西方饮食（WD）诱导的肥胖如何影响每个过程，以及自愿进行体育活动是否可以缓解线粒体质量控制机制的紊乱。尽管WD后线粒体含量增加（细胞色素氧化酶亚基IV和细胞色素C），但生物发生调控因子的诱导似乎受损（过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）诱导失败）。线粒体融合似乎减少（线粒体融合蛋白2（MFN2）、视神经萎缩蛋白1（Opa1）蛋白减少），而分裂没有显著变化，这表明动力学调节平衡向有利于分裂的方向转变。WD促进了自噬通量（p62减少，微管相关蛋白1轻链3-II/微管相关蛋白1轻链3-I（LC3II:I）比值增加）；然而，WD中线粒体自噬标志物BNIP3减少，这可能表明尽管总自噬通量增加，但线粒体自噬减少。WD使MPTP调节因子腺苷酸转位酶（Ant）mRNA减少。很少有过程受到体育活动的影响。最后，PGC-1α部分促进了线粒体质量控制过程，因为PGC-1α转基因小鼠表现出线粒体生物发生和自噬通量增加。此外，这些小鼠的MFN1和Opa1 mRNA升高，而蛋白质含量没有变化，这表明这些因子通过PGC-1α过表达在转录水平上得到促进。这些数据表明肥胖状态下线粒体质量控制存在功能障碍，并且PGC-1α足以促进线粒体质量控制的多个方面，但不一定是所有方面。因此，线粒体质量控制可能是治疗代谢性疾病的一个合适靶点。