Dysregulation of the Mitochondrial Proteome Occurs in Mice Lacking Adiponectin Receptor 1
Dysregulation of the Mitochondrial Proteome Occurs in Mice Lacking Adiponectin Receptor 1
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DOI：
10.3389/fendo.2019.00872
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发表时间：
2019-12-13
影响因子：
5.2
通讯作者：
Bugger, Heiko
中科院分区：
文献类型：
--
作者：
Pepin, Mark E.;Koentges, Christoph;Bugger, Heiko
2 型糖尿病患者血清脂联素水平降低，通过受损的脂联素受体 1 (AdipoR1) 信号传导损害 AMPK-SIRT1-PGC-1 α 信号传导，从而与糖尿病并发症中线粒体功能障碍的发生有关。在这里，我们的目的是描述先前未定义的 AdipoR1 信号中断对心脏、肾和肝组织线粒体蛋白组成的作用，这三个器官主要与糖尿病并发症相关。在从 Adipor1(-/-) 小鼠的心脏、肾脏和肝脏分离的线粒体中进行比较蛋白质组学。在心脏、肾和肝线粒体中分别鉴定出总共 790、1,573 和 1,833 个蛋白质。而 Adipor1(-/-) 小鼠的心脏、肾和肝组织中分别有 121、98 和 78 个蛋白质受到差异调节；在所有研究的组织中，只有 15 种蛋白质受到相同方向的调节。差异表达蛋白质的富集分析揭示了跨组织类型保守的参与氧化磷酸化的蛋白质的不成比例的代表性。精心策划的通路分析确定 HNF4、NRF1、LONP、RICTOR、SURF1、胰岛素受体和 PGC-1 α 为候选上游调节因子。在肥胖和胰岛素抵抗的高脂喂养非转基因小鼠中，与低脂喂养小鼠相比，心脏（-70%）、肾脏（-80%）和肝脏（-90%）中AdipoR1基因表达显着降低（均P < 0.05）。 NRF1 是 Adipor1(-/-) 小鼠和高脂肪喂养小鼠中唯一下调的上游调节因子，这表明了共同的调节机制。因此，AdipoR1 信号传导以功能保守但分子上不同的方式调节所有研究组织中的线粒体蛋白质组成。讨论了 AdipoR1 信号传导受损的生物学意义和潜在影响。
Decreased serum adiponectin levels in type 2 diabetes has been linked to the onset of mitochondrial dysfunction in diabetic complications by impairing AMPK-SIRT1-PGC-1 alpha signaling via impaired adiponectin receptor 1 (AdipoR1) signaling. Here, we aimed to characterize the previously undefined role of disrupted AdipoR1 signaling on the mitochondrial protein composition of cardiac, renal, and hepatic tissues as three organs principally associated with diabetic complications. Comparative proteomics were performed in mitochondria isolated from the heart, kidneys and liver of Adipor1(-/-) mice. A total of 790, 1,573, and 1,833 proteins were identified in cardiac, renal and hepatic mitochondria, respectively. While 121, 98, and 78 proteins were differentially regulated in cardiac, renal, and hepatic tissue of Adipor1(-/-) mice, respectively; only 15 proteins were regulated in the same direction across all investigated tissues. Enrichment analysis of differentially expressed proteins revealed disproportionate representation of proteins involved in oxidative phosphorylation conserved across tissue types. Curated pathway analysis identified HNF4, NRF1, LONP, RICTOR, SURF1, insulin receptor, and PGC-1 alpha as candidate upstream regulators. In high fat-fed non-transgenic mice with obesity and insulin resistance, AdipoR1 gene expression was markedly reduced in heart (-70%), kidney (-80%), and liver (-90%) (all P < 0.05) as compared to low fat-fed mice. NRF1 was the only upstream regulator downregulated both in Adipor1(-/-) mice and in high fat-fed mice, suggesting common mechanisms of regulation. Thus, AdipoR1 signaling regulates mitochondrial protein composition across all investigated tissues in a functionally conserved, yet molecularly distinct, manner. The biological significance and potential implications of impaired AdipoR1 signaling are discussed.