The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer.

IF 2.9 4区 生物学 Q2 BIOPHYSICS
Thomas N Seyfried, Derek C Lee, Tomas Duraj, Nathan L Ta, Purna Mukherjee, Michael Kiebish, Gabriel Arismendi-Morillo, Christos Chinopoulos
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引用次数: 0

Abstract

Otto Warburg originally proposed that cancer arose from a two-step process. The first step involved a chronic insufficiency of mitochondrial oxidative phosphorylation (OxPhos), while the second step involved a protracted compensatory energy synthesis through lactic acid fermentation. His extensive findings showed that oxygen consumption was lower while lactate production was higher in cancerous tissues than in non-cancerous tissues. Warburg considered both oxygen consumption and extracellular lactate as accurate markers for ATP production through OxPhos and glycolysis, respectively. Warburg's hypothesis was challenged from findings showing that oxygen consumption remained high in some cancer cells despite the elevated production of lactate suggesting that OxPhos was largely unimpaired. New information indicates that neither oxygen consumption nor lactate production are accurate surrogates for quantification of ATP production in cancer cells. Warburg also did not know that a significant amount of ATP could come from glutamine-driven mitochondrial substrate level phosphorylation in the glutaminolysis pathway with succinate produced as end product, thus confounding the linkage of oxygen consumption to the origin of ATP production within mitochondria. Moreover, new information shows that cytoplasmic lipid droplets and elevated aerobic lactic acid fermentation are both biomarkers for OxPhos insufficiency. Warburg's original hypothesis can now be linked to a more complete understanding of how OxPhos insufficiency underlies dysregulated cancer cell growth. These findings can also address several questionable assumptions regarding the origin of cancer thus allowing the field to advance with more effective therapeutic strategies for a less toxic metabolic management and prevention of cancer.

Warburg假说和线粒体代谢癌症理论的出现。
奥托·沃伯格最初提出,癌症的产生有两个步骤。第一步涉及线粒体氧化磷酸化(OxPhos)的慢性不足,而第二步涉及通过乳酸发酵的长期代偿性能量合成。他广泛的研究结果表明,癌组织的耗氧量比非癌组织低,而乳酸产量比非癌组织高。Warburg认为氧气消耗和细胞外乳酸分别是通过OxPhos和糖酵解产生ATP的准确标记。Warburg的假设受到了一些研究结果的挑战,这些研究表明,尽管乳酸含量升高,但一些癌细胞的耗氧量仍然很高,这表明OxPhos基本上没有受损。新的信息表明,无论是氧气消耗还是乳酸产生都不能准确地代替癌细胞中ATP产生的定量。Warburg也不知道在谷氨酰胺水解途径中,大量的ATP可能来自谷氨酰胺驱动的线粒体底物水平磷酸化,最终产生琥珀酸盐,从而混淆了线粒体内氧气消耗与ATP产生起源的联系。此外,新的信息表明,细胞质脂滴和有氧乳酸发酵升高都是OxPhos不足的生物标志物。Warburg最初的假设现在可以与对OxPhos不足如何导致癌细胞生长失调的更全面的理解联系起来。这些发现也可以解决一些关于癌症起源的可疑假设,从而使该领域能够推进更有效的治疗策略,以实现毒性更小的代谢管理和癌症预防。
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来源期刊
CiteScore
6.00
自引率
0.00%
发文量
22
审稿时长
6-12 weeks
期刊介绍: The Journal of Bioenergetics and Biomembranes is an international journal devoted to the publication of original research that contributes to fundamental knowledge in the areas of bioenergetics, biomembranes, and transport, including oxidative phosphorylation, photosynthesis, muscle contraction, as well as cellular and systemic metabolism. The timely research in this international journal benefits biophysicists, membrane biologists, cell biologists, biochemists, molecular biologists, physiologists, endocrinologists, and bio-organic chemists.
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