Glioblastoma multiforme (GBM) is the most common and malignant of the primary adult brain cancers. Ultrastructural and biochemical evidence shows that GBM cells exhibit mitochondrial abnormalities incompatible with energy production through oxidative phosphorylation (OxPhos). Under such conditions, the mitochondrial F0-F1 ATP synthase operates in reverse at the expense of ATP hydrolysis to maintain a moderate membrane potential. Moreover, expression of the dimeric M2 isoform of pyruvate kinase in GBM results in diminished ATP output, precluding a significant ATP production from glycolysis. If ATP synthesis through both glycolysis and OxPhos was impeded, then where would GBM cells obtain high-energy phosphates for growth and invasion? Literature is reviewed suggesting that the succinate-CoA ligase reaction in the tricarboxylic acid cycle can substantiate sufficient ATP through mitochondrial substrate-level phosphorylation (mSLP) to maintain GBM growth when OxPhos is impaired. Production of high-energy phosphates would be supported by glutaminolysis-a hallmark of GBM metabolism-through the sequential conversion of glutamine → glutamate → alpha-ketoglutarate → succinyl CoA → succinate. Equally important, provision of ATP through mSLP would maintain the adenine nucleotide translocase in forward mode, thus preventing the reverse-operating F0-F1 ATP synthase from depleting cytosolic ATP reserves. Because glucose and glutamine are the primary fuels driving the rapid growth of GBM and most tumors for that matter, simultaneous restriction of these two substrates or inhibition of mSLP should diminish cancer viability, growth, and invasion.

中文翻译：

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线粒体底物水平的磷酸化作为胶质母细胞瘤的能源：回顾与假设。

多形胶质母细胞瘤（GBM）是主要的成人脑癌中最常见和最恶性的。超微结构和生化证据表明，GBM细胞表现出线粒体异常，与通过氧化磷酸化（OxPhos）产生的能量不相容。在这种条件下，线粒体F0-F1 ATP合酶以ATP水解为代价反向运行，以维持适度的膜电位。此外，丙酮酸激酶的二聚体M2同工型在GBM中的表达导致ATP输出减少，从而排除了糖酵解产生的大量ATP。如果通过糖酵解和OxPhos阻止ATP合成，那么GBM细胞将在哪里获得高能磷酸盐来生长和侵袭？文献综述表明，三羧酸循环中的琥珀酸辅酶A连接酶反应可通过线粒体底物水平的磷酸化（mSLP）来证实足够的ATP，从而在OxPhos受损时维持GBM的生长。高能磷酸盐的生产将通过谷氨酰胺→谷氨酸→α-酮戊二酸酯→琥珀酰辅酶A→琥珀酸酯的顺序转化得到谷氨酰胺分解（GBM代谢的标志）来支持。同样重要的是，通过mSLP提供ATP将使腺嘌呤核苷酸的转位酶保持正向模式，从而防止反向操作的F0-F1 ATP合酶消耗胞浆中的ATP储备。