ATP/ADP ratio, the missed connection between mitochondria and the Warburg effect.
ATP/ADP ratio, the missed connection between mitochondria and the Warburg effect.
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DOI：
10.1016/j.mito.2014.09.002
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发表时间：
2014-11
期刊：
影响因子：
4.4
通讯作者：
Lemasters, John J.
中科院分区：
文献类型：
--
作者：
Maldonado, Eduardo N.;Lemasters, John J.
非增殖细胞通过完全氧化线粒体中的呼吸底物来产生大量的细胞ATP。呼吸底物仅通过电压依赖性阴离子通道（VDAC）一个通道穿过线粒体外膜。一旦进入基质，呼吸底物在三羧酸循环中被氧化，主要生成NADH，NADH在呼吸链中被进一步氧化，生成主要由膜电位（Δ P）组成的质子动力，以合成ATP。然后，线粒体ΔΨ通过位于线粒体内膜的腺嘌呤核苷酸转运蛋白（ANT）驱动ATP-4从基质中释放，以交换胞质中的ADP-3。因此，非增殖细胞中的线粒体功能驱动高胞质ATP/ADP比率，这对于抑制糖酵解至关重要。相比之下，增殖细胞的瓦尔堡表型的生物能量学的特征在于有氧糖酵解的增强和线粒体代谢的抑制。抑制线粒体功能导致线粒体ATP的产生降低，因此细胞溶质ATP/ADP比率降低，有利于糖酵解的增强。因此，胞质ATP/ADP比率是决定细胞代谢主要是氧化还是糖酵解的关键特征。在这里，我们描述了两种新的机制来解释抑制癌细胞中的线粒体代谢：相对关闭的VDAC的自由微管蛋白和ANT的失活。这两种机制都有助于激活糖酵解的低ATP/ADP比率。
Non-proliferating cells generate the bulk of cellular ATP by fully oxidizing respiratory substrates in mitochondria. Respiratory substrates cross the mitochondrial outer membrane through only one channel, the voltage dependent anion channel (VDAC). Once in the matrix, respiratory substrates are oxidized in the tricarboxylic acid cycle to generate mostly NADH that is further oxidized in the respiratory chain to generate a proton motive force comprised mainly of membrane potential (ΔΨ) to synthesize ATP. Mitochondrial ΔΨ then drives release of ATP−4 from the matrix in exchange for ADP−3 in the cytosol via the adenine nucleotide translocator (ANT) located in the mitochondrial inner membrane. Thus, mitochondrial function in non-proliferating cells drives a high cytosolic ATP/ADP ratio, essential to inhibit glycolysis. By contrast, the bioenergetics of the Warburg phenotype of proliferating cells is characterized by enhanced aerobic glycolysis and suppression of mitochondrial metabolism. Suppressed mitochondrial function leads to lower production of mitochondrial ATP and hence lower cytosolic ATP/ADP ratios that favor enhanced glycolysis. Thus, cytosolic ATP/ADP ratio is a key feature that determines if cell metabolism is predominantly oxidative or glycolytic. Here, we describe two novel mechanisms to explain the suppression of mitochondrial metabolism in cancer cells: the relative closure of VDAC by free tubulin and inactivation of ANT. Both mechanisms contribute to low ATP/ADP ratios that activate glycolysis.
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