Warburg effect has been recognized as a hallmark of cancer cells for many years, but its modulation mechanism remains a great focus. Our current study found a member of solute carrier family 25 (SLC25A29), the main arginine transporter on mitochondria, significantly elevated in various cancer cells. Knockout of SLC25A29 by CRISPR/Cas9 inhibited proliferation and migration of cancer cells both in vitro and in vivo. SLC25A29-knockout cells also showed an altered metabolic status with enhanced mitochondrial respiration and reduced glycolysis. All of above impacts could be reversed after rescuing SLC25A29 expression in SLC25A29-knockout cells. Arginine is transported into mitochondria partly for nitric oxide (NO) synthesis. Deletion of SLC25A29 resulted in severe decrease of NO production, indicating that the mitochondria is a significant source of NO. SLC25A29-knockout cells dramatically altered the variation of metabolic processes, whereas addition of arginine failed to reverse the effect, highlighting the necessity of transporting arginine into mitochondria by SLC25A29. In conclusion, aberrant elevated SLC25A29 in cancer functioned to transport more arginine into mitochondria, improved mitochondria-derived NO levels, thus modulated metabolic status to facilitate increased cancer progression.

中文翻译：

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癌症中线粒体SLC25A29的升高通过增加线粒体衍生的一氧化氮来调节代谢状态。

沃堡效应已经被公认为是癌细胞的标志，但是其调节机制仍然是人们关注的焦点。我们当前的研究发现，溶质载体家族25（SLC25A29）的成员是线粒体上的主要精氨酸转运蛋白，在各种癌细胞中均显着升高。CRISPR / Cas9敲除SLC25A29可在体内外抑制癌细胞的增殖和迁移。SLC25A29基因敲除细胞还显示出代谢状态改变，线粒体呼吸增强，糖酵解减少。在挽救SLC25A29基因敲除细胞中的SLC25A29表达后，上述所有影响都可以逆转。精氨酸部分转运到线粒体中，以合成一氧化氮（NO）。SLC25A29的缺失导致NO产生的严重减少，表明线粒体是NO的重要来源。SLC25A29基因敲除细胞极大地改变了代谢过程的变化，而添加精氨酸则不能逆转这种作用，这突出表明了SLC25A29将精氨酸转运到线粒体中的必要性。总之，癌症中异常升高的SLC25A29的功能是将更多的精氨酸转运到线粒体中，改善了线粒体衍生的NO水平，从而调节了代谢状态，从而促进了癌症的发展。