In contrast to the "Warburg effect" or aerobic glycolysis earlier generalized as a phenomenon in cancer cells, more and more recent evidence indicates that functional mitochondria are pivotal for ensuring the energy supply of cancer cells. Here, we report that cancer cells with reduced autophagy-related protein 12 (ATG12) expression undergo an oncotic cell death, a phenotype distinct from that seen in ATG5-deficient cells described before. In addition, using untargeted metabolomics with ATG12-deficient cancer cells, we observed a global reduction in cellular bioenergetic pathways, such as β-oxidation (FAO), glycolysis, and tricarboxylic acid cycle activity, as well as a decrease in mitochondrial respiration as monitored with Seahorse experiments. Analyzing the biogenesis of mitochondria by quantifying mitochondrial DNA content together with several mitochondrion-localizing proteins indicated a reduction in mitochondrial biogenesis in ATG12-deficient cancer cells, which also showed reduced hexokinase II expression and the upregulation of uncoupling protein 2. ATG12, which we observed in normal cells to be partially localized in mitochondria, is upregulated in multiple types of solid tumors in comparison with normal tissues. Strikingly, mouse xenografts of ATG12-deficient cells grew significantly slower as compared with vector control cells. Collectively, our work has revealed a previously unreported role for ATG12 in regulating mitochondrial biogenesis and cellular energy metabolism and points up an essential role for mitochondria as a failsafe mechanism in the growth and survival of glycolysis-dependent cancer cells. Inducing oncosis by imposing an ATG12 deficiency in solid tumors might represent an anticancer therapy preferable to conventional caspase-dependent apoptosis that often leads to undesirable consequences, such as incomplete cancer cell killing and a silencing of the host immune system.

中文翻译：

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由于线粒体生物合成减少和细胞生物能减少，ATG12 缺陷会导致肿瘤细胞癌变。

与早期普遍认为癌细胞中的一种现象“瓦尔堡效应”或有氧糖酵解相反，越来越多的最新证据表明，功能性线粒体对于确保癌细胞的能量供应至关重要。在这里，我们报告自噬相关蛋白 12 (ATG12) 表达减少的癌细胞会经历胶体细胞死亡，这种表型与之前描述的 ATG5 缺陷细胞中所见的表型不同。此外，通过对 ATG12 缺陷的癌细胞进行非靶向代谢组学分析，我们观察到细胞生物能量途径的整体减少，例如 β-氧化 (FAO)、糖酵解和三羧酸循环活性，以及​​监测到的线粒体呼吸减少与海马实验。通过定量线粒体 DNA 含量和几种线粒体定位蛋白来分析线粒体的生物发生，表明 ATG12 缺陷的癌细胞中线粒体生物发生减少，这也表明己糖激酶 II 表达减少以及解偶联蛋白 2. ATG12 的上调，我们观察到在正常细胞中，部分位于线粒体中，与正常组织相比，在多种类型的实体瘤中表达上调。引人注目的是，与载体对照细胞相比，ATG12 缺陷细胞的小鼠异种移植物生长速度明显减慢。总的来说，我们的工作揭示了 ATG12 在调节线粒体生物合成和细胞能量代谢中先前未报道的作用，并指出线粒体作为糖酵解依赖性癌细胞生长和存活的故障安全机制的重要作用。通过在实体瘤中施加 ATG12 缺陷来诱导肿瘤形成可能是一种优于传统 caspase 依赖性细胞凋亡的抗癌疗法，传统的 caspase 依赖性细胞凋亡通常会导致不良后果，例如不完全杀死癌细胞和宿主免疫系统沉默。