文章：

线粒体与癌症

Mitochondria and cancer

原文发布日期：2012-09-24

DOI: 10.1038/nrc3365

类型: Review Article

开放获取: 否

要点：

1. Warburg observed, 70 years ago, that tumours produce excess lactate in the presence of oxygen. This became known as aerobic glycolysis or the 'Warburg effect' which he interpreted as mitochondrial dysfunction. However, it is now clear that mitochondrial function is essential for cancer cell viability, because elimination of cancer cell mitochondrial DNAs (mtDNAs) reduces their growth rate and tumorigenicity.
2. The mitochondrial genome encompasses thousands of copies of the mtDNA and more than one thousand nuclear DNA (nDNA)-encoded genes. mtDNA mutations have been found in various cancers and seem to alter mitochondrial metabolism, enhance tumorigenesis and permit cancer cell adaptation to changing environments.
3. Mutations in nDNA genes involved in mitochondrial metabolism, including succinate dehydrogenase (SDH), fumarate hydratase (FH), isocitrate dehydrogenase 1 (IDH1) and IDH2, result in increased succinate, fumarate, or R(-)-2-hydroxyglutarate levels. These metabolic alterations can inhibit various α-ketoglutarate-dependent dioxygenases; they can also activate the NFE2-related factor 2 (NRF2) stress response pathway. All of these effects can contribute to tumorigenesis.
4. Activation of signalling pathways and oncogenes that are known to be important in tumorigenesis also affect mitochondrial function. The PI3K–PTEN–AKT pathway shifts metabolism from oxidative to glycolytic, thus permitting the redistribution of glycolytic nutrients from catabolism to anabolism. Activation of MYC induces glutaminolysis, which provides anaplerotic substrates to the mitochondrial tricarboxylic acid cycle, thus enhancing citrate production and its export to the cytosol to provide acetyl-CoA for lipid biogenesis and protein modifications.
5. Altered mitochondrial metabolism can increase the production of mitochondrial reactive oxygen species (ROS) and change the cellular redox status, thus altering the activities of transcription factors such as HIF1α and FOS–JUN to change gene expression and stimulate cancer cell proliferation.
6. A decrease of the mitochondrial membrane potential or mutation of the promyelocytic leukaemia (PML) gene reduces mitochondrial Ca²⁺ uptake, thus decreasing the activation of the mitochondrial intrinsic apoptosis pathway.
7. Reduced mitochondrial Ca²⁺ retention increases the cytosolic Ca²⁺ concentration. This activates mitochondrial retrograde signalling through stimulation of calcineurin and IκBβ-dependent NF-κB, activation of enhanceosome-driven transcription and increased metastatic potential.
8. Cancer cell ROS production inactivates caveolin 1 in adjacent stromal fibroblasts. This increases mitophagy, reduces mitochondrial function and increases lactate production in these fibroblasts. Secreted stromal cell lactate then fuels cancer cell oxidative metabolism, which drives tumour growth and proliferation. This is known as the 'reverse Warburg effect'.

要点翻译：

1. 瓦伯格在70年前观察到，肿瘤在氧气存在下会产生过量乳酸。这一现象被称为有氧糖酵解或“瓦伯格效应”，他将其解释为线粒体功能障碍。然而，现在已明确线粒体功能对癌细胞的存活至关重要，因为清除癌细胞线粒体DNA会降低其生长速率和致瘤性。
2. 线粒体基因组包含数千份线粒体DNA拷贝和一千多个核DNA编码基因。多种癌症中均发现线粒体DNA突变，这些突变似乎会改变线粒体代谢、增强肿瘤发生并促进癌细胞适应环境变化。
3. 参与线粒体代谢的核DNA基因突变（包括琥珀酸脱氢酶、富马酸水合酶、异柠檬酸脱氢酶1和IDH2）会导致琥珀酸、富马酸或R(-)-2-羟基戊二酸水平升高。这些代谢变化可抑制多种α-酮戊二酸依赖的双加氧酶，也能激活NRF2应激反应通路。所有这些效应都可能促进肿瘤发生。
4. 已知在肿瘤发生中重要的信号通路和癌基因的激活也会影响线粒体功能。PI3K-PTEN-AKT通路将代谢从氧化磷酸化转向糖酵解，从而使糖酵解营养物质从分解代谢重新分配到合成代谢。MYC激活会诱导谷氨酰胺分解，为线粒体三羧酸循环提供回补底物，从而增强柠檬酸生成及其向胞质的输出，为脂质生物合成和蛋白质修饰提供乙酰辅酶A。
5. 线粒体代谢改变会增加线粒体活性氧的生成并改变细胞氧化还原状态，从而改变HIF1α和FOS-JUN等转录因子的活性，最终改变基因表达并刺激癌细胞增殖。
6. 线粒体膜电位降低或早幼粒细胞白血病基因突变会减少线粒体Ca2+摄取，从而降低线粒体内在凋亡通路的激活。
7. 线粒体Ca2+滞留减少会提高胞质Ca2+浓度。这通过刺激钙调神经磷酸酶和IκBβ依赖性NF-κB激活线粒体逆行信号传导，增强体驱动转录的激活并增加转移潜能。
8. 癌细胞的ROS生成会使邻近基质成纤维细胞中的小窝蛋白1失活。这增加了这些成纤维细胞中的线粒体自噬，降低线粒体功能并增加乳酸生成。分泌的基质细胞乳酸随后为癌细胞氧化代谢提供燃料，从而驱动肿瘤生长和增殖。这一过程被称为“反向瓦伯格效应”。

英文摘要：

Contrary to conventional wisdom, functional mitochondria are essential for the cancer cell. Although mutations in mitochondrial genes are common in cancer cells, they do not inactivate mitochondrial energy metabolism but rather alter the mitochondrial bioenergetic and biosynthetic state. These states communicate with the nucleus through mitochondrial 'retrograde signalling' to modulate signal transduction pathways, transcriptional circuits and chromatin structure to meet the perceived mitochondrial and nuclear requirements of the cancer cell. Cancer cells then reprogramme adjacent stromal cells to optimize the cancer cell environment. These alterations activate out-of-context programmes that are important in development, stress response, wound healing and nutritional status.

摘要翻译： 

与传统观点相反，功能性线粒体对癌细胞至关重要。尽管线粒体基因突变在癌细胞中很常见，但这些突变并未使线粒体能量代谢失活，而是改变了线粒体的生物能量和生物合成状态。这些状态通过线粒体“逆行信号”与细胞核通信，从而调节信号转导通路、转录回路和染色质结构，以满足癌细胞对线粒体和细胞核的感知需求。癌细胞随后会重编程邻近的基质细胞，以优化癌细胞所处的环境。这些改变激活了在发育、应激反应、伤口愈合和营养状态中原本重要但此时脱离正常语境的程序。

原文链接：

Mitochondria and cancer