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FOXK1 and FOXK2 regulate aerobic glycolysis

机译：FOXK1和FOXK2调节有氧糖酵解

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Adaptation to the environment and extraction of energy are essential for survival. Some species have found niches and specialized in using a particular source of energy, whereas others-including humans and several other mammals-have developed a high degree of flexibility(1). A lot is known about the general metabolic fates of different substrates but we still lack a detailed mechanistic understanding of how cells adapt in their use of basic nutrients(2). Here we show that the closely related fasting/starvation-induced forkhead transcription factors FOXK1 and FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this (for example, hexokinase-2, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase), while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyruvate dehydrogenase kinases 1 and 4. Together with suppression of the catalytic subunit of pyruvate dehydrogenase phosphatase 1 this leads to increased phosphorylation of the E1 alpha regulatory subunit of the pyruvate dehydrogenase complex, which in turn inhibits further oxidation of pyruvate in the mitochondria-instead, pyruvate is reduced to lactate. Suppression of FOXK1 and FOXK2 induce the opposite phenotype. Both in vitro and in vivo experiments, including studies of primary human cells, show how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis.
机译：适应环境和提取能量对于生存至关重要。一些物种发现了壁ni，并专门使用特定的能源，而其他物种（包括人类和其他几种哺乳动物）则具有高度的灵活性（1）。关于不同底物的一般代谢命运，人们了解很多，但我们仍然缺乏对细胞如何适应其基本营养素利用的详细机械理解（2）。在这里，我们显示紧密相关的禁食/饥饿诱导的叉头转录因子FOXK1和FOXK2通过上调为此所需的酶机制（例如，己糖激酶-2，磷酸果糖激酶，丙酮酸激酶和乳酸脱氢酶）来诱导有氧糖酵解。同时通过增加丙酮酸脱氢酶激酶1和4的活性来抑制线粒体内丙酮酸的进一步氧化。同时抑制丙酮酸脱氢酶磷酸酶1的催化亚基，这会导致丙酮酸脱氢酶复合物的E1α调节亚基的磷酸化增加。继而抑制了线粒体中丙酮酸的进一步氧化，相反，丙酮酸被还原为乳酸。 FOXK1和FOXK2的抑制诱导相反的表型。体外和体内实验（包括对人类原代细胞的研究）均显示FOXK1和/或FOXK2可能如何充当重编程细胞代谢以诱导有氧糖酵解的重要调节剂。

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