Atsushi Watanabe, Chartsiam Tipgomut, Haruhito Totani, Kentaro Yoshimura, Tomohiko Iwano, Hamed Bashiri, Lee Hui Chua, Chong Yang, Toshio Suda
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引用次数: 0
摘要
癌细胞依赖线粒体氧化磷酸化(OXPHOS)和非典型三羧酸(TCA)循环。在本文中,我们揭示了非典型三羧酸循环在宿主侧向线粒体让步中扮演的重要角色,尤其是在高能量需求的恶性肿瘤细胞中。抑制非典型 TCA 循环中的关键酶 ATP 柠檬酸酶(ACLY)会增加活性氧水平和 DNA 损伤,同时降低线粒体膜电位,从而诱导细胞凋亡。线粒体膜柠檬酸盐转运体抑制剂 CTPI2 协同增强了这些效应。ACLY 抑制剂降低了细胞膜柠檬酸盐水平,而 CTPI2 则降低了 ACLY 的活性,这表明非典型 TCA 循环是通过正反馈机制维持的。这些抑制作用损害了 ATP 的产生,尤其是通过 OXPHOS 产生的 ATP。线粒体和细胞质组分的代谢组学分析表明,非典型 TCA 循环抑制后,线粒体中谷胱甘肽途径相关代谢物和 TCA 循环相关代谢物(富马酸除外)的水平降低。尽管线粒体能有效地为细胞提供能量,但这种共生关系也带来了与活性氧和线粒体维护有关的挑战。总之,非典型 TCA 循环对典型 TCA 循环和线粒体的完整性不可或缺,有助于线粒体的驯化。
Noncanonical TCA cycle fosters canonical TCA cycle and mitochondrial integrity in acute myeloid leukemia.
Cancer cells rely on mitochondrial oxidative phosphorylation (OXPHOS) and the noncanonical tricarboxylic acid (TCA) cycle. In this paper, we shed light on the vital role played by the noncanonical TCA cycle in a host-side concession to mitochondria, especially in highly energy-demanding malignant tumor cells. Inhibition of ATP-citrate lyase (ACLY), a key enzyme in the noncanonical TCA cycle, induced apoptosis by increasing reactive oxygen species levels and DNA damage while reducing mitochondrial membrane potential. The mitochondrial membrane citrate transporter inhibitor, CTPI2, synergistically enhanced these effects. ACLY inhibition reduced cytosolic citrate levels and CTPI2 lowered ACLY activity, suggesting that the noncanonical TCA cycle is sustained by a positive feedback mechanism. These inhibitions impaired ATP production, particularly through OXPHOS. Metabolomic analysis of mitochondrial and cytosolic fractions revealed reduced levels of glutathione pathway-related and TCA cycle-related metabolite, except fumarate, in mitochondria following noncanonical TCA cycle inhibition. Despite the efficient energy supply to the cell by mitochondria, this symbiosis poses challenges related to reactive oxygen species and mitochondrial maintenance. In conclusion, the noncanonical TCA cycle is indispensable for the canonical TCA cycle and mitochondrial integrity, contributing to mitochondrial domestication.
期刊介绍:
Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports.
Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.