GCN5L1 modulates cross-talk between mitochondria and cell signaling to regulate FoxO1 stability and gluconeogenesis.
GCN5L1 modulates cross-talk between mitochondria and cell signaling to regulate FoxO1 stability and gluconeogenesis.
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DOI：
10.1038/s41467-017-00521-8
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发表时间：
2017-09-12
影响因子：
16.6
通讯作者：
Sack MN
中科院分区：
文献类型：
--
作者：
Wang L;Scott I;Zhu L;Wu K;Han K;Chen Y;Gucek M;Sack MN
线粒体富集的gcn5样1 （GCN5L1）蛋白已被证明可调节线粒体蛋白乙酰化、线粒体含量和线粒体逆行信号传导。本研究表明，肝脏GCN5L1消融可降低空腹血糖水平，并在不影响全身葡萄糖耐量的情况下减弱肝脏糖异生。GCN5L1肝脏特异性敲除小鼠肝细胞中的PEPCK和G6Pase转录水平下调，其上游调节因子FoxO1蛋白水平通过蛋白酶体依赖性降解和活性氧介导的ERK-1/2磷酸化而降低。ERK抑制恢复fox01、糖异生酶表达和葡萄糖生成。线粒体靶向GCN5L1的重建减弱了线粒体ROS、ERK的激活，增加了fox01、糖异生酶的表达和肝细胞葡萄糖的产生。我们认为，线粒体GCN5L1通过线粒体ROS介导的ERK激活调节fox01的翻译后控制，调节糖异生并控制代谢途径。探索GCN5L1介导的ROS信号传导的机制可能会扩大我们对线粒体在糖异生控制中的作用的理解。肝脏糖异生在转录水平受到严格调控，对长时间禁食期间的生存至关重要。Wang等人发现，线粒体富集的gcn5样1蛋白通过蛋白酶体依赖性降解调控fox01蛋白水平，进而调控糖异生基因表达，从而控制肝脏葡萄糖的产生。
The mitochondrial enriched GCN5-like 1 (GCN5L1) protein has been shown to modulate mitochondrial protein acetylation, mitochondrial content and mitochondrial retrograde signaling. Here we show that hepatic GCN5L1 ablation reduces fasting glucose levels and blunts hepatic gluconeogenesis without affecting systemic glucose tolerance. PEPCK and G6Pase transcript levels are downregulated in hepatocytes from GCN5L1 liver specific knockout mice and their upstream regulator, FoxO1 protein levels are decreased via proteasome-dependent degradation and via reactive oxygen species mediated ERK-1/2 phosphorylation. ERK inhibition restores FoxO1, gluconeogenic enzyme expression and glucose production. Reconstitution of mitochondrial-targeted GCN5L1 blunts mitochondrial ROS, ERK activation and increases FoxO1, gluconeogenic enzyme expression and hepatocyte glucose production. We suggest that mitochondrial GCN5L1 modulates post-translational control of FoxO1, regulates gluconeogenesis and controls metabolic pathways via mitochondrial ROS mediated ERK activation. Exploring mechanisms underpinning GCN5L1 mediated ROS signaling may expand our understanding of the role of mitochondria in gluconeogenesis control. Hepatic gluconeogenesis is tightly regulated at transcriptional level and is essential for survival during prolonged fasting. Here Wang et al. show that the mitochondrial enriched GCN5-like 1 protein controls hepatic glucose production by regulating FoxO1 protein levels via proteasome-dependent degradation and, in turn, gluconeogenic gene expression.
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