Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase
Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase
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DOI：
10.1101/gad.889901
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发表时间：
2001-06-01
影响因子：
10.5
通讯作者：
Hay, N
中科院分区：
文献类型：
--
作者：
Gottlob, K;Majewski, N;Hay, N
丝氨酸/苏氨酸激酶Akt/PKB是生长因子介导的细胞存活的主要下游效应物。活化的Akt与Bcl - 2和Bcl - xL一样，可阻止一种通透性转换（PT）孔成分——电压依赖性阴离子通道（VDAC）的关闭、细胞内酸化、线粒体超极化以及细胞色素c释放之前氧化磷酸化的下降。然而，与Bcl - 2和Bcl - xL不同的是，活化的Akt维持线粒体完整性从而抑制细胞凋亡的能力需要葡萄糖的供应，并与其代谢相关。已知己糖激酶可与VDAC结合，并将线粒体内的ATP合成与葡萄糖代谢直接偶联。我们提供的证据表明，这种偶联是Akt的一种下游效应功能。首先，Akt增加与线粒体相关的己糖激酶活性。其次，Akt的抗凋亡活性仅需要己糖激酶催化的葡萄糖代谢的第一步关键反应。最后，异位表达己糖激酶可模拟Akt抑制细胞色素c释放和细胞凋亡的能力。因此，我们提出Akt通过促进线粒体外膜上己糖激酶 - VDAC的相互作用，增强葡萄糖代谢与氧化磷酸化的偶联，并调节PT孔的开放。
The serine/threonine kinase Akt/PKB is a major downstream effector of growth factor-mediated cell survival. Activated Akt, like Bcl-2 and Bcl-xL, prevents closure of a PT pore component, the voltage-dependent anion channel (VDAC); intracellular acidification; mitochondrial hyperpolarization and the decline in oxidative phosphorylation that precedes cytochrome c release. However, unlike Bcl-2 and Bcl-xL, the ability of activated Akt to preserve mitochondrial integrity, and thereby inhibit apoptosis, requires glucose availability and is coupled to its metabolism. Hexokinases are known to bind to VDAC and directly couple intramitochondrial ATP synthesis to glucose metabolism, We provide evidence that such coupling serves as a downstream effector function for Akt. First, Akt increases mitochondria-associated hexokinase activity. Second, the antiapoptotic activity of Akt requires only the first committed step of glucose metabolism catalyzed by hexokinase. Finally, ectopic hexokinase expression mimics the ability of Akt to inhibit cytochrome c release and apoptosis. We therefore propose that Akt increases coupling of glucose metabolism to oxidative phosphorylation and regulates PT pore opening via the promotion of hexokinase-VDAC interaction at the outer mitochondrial membrane.