Department of Molecular and Cellular Endocrinology, Diabetes and Metabolism Research Institute, City of Hope Medical Center, Duarte, CA, 91010, USA.
Departments of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, 91010, USA.
Br J Cancer. 2020 Apr;122(9):1288-1297. doi: 10.1038/s41416-020-0778-x. Epub 2020 Mar 9.
Previous studies suggested that mdivi-1 (mitochondrial division inhibitor), a putative inhibitor of dynamin-related protein (DRP1), decreased cancer cell proliferation through inducing mitochondrial fusion and altering oxygen consumption. However, the metabolic reprogramming underlying the DRP1 inhibition is still unclear in cancer cells.
To better understand the metabolic effect of DRP1 inhibition, [U-C]glucose isotope tracing was employed to assess mdivi-1 effects in several cancer cell lines, DRP1-WT (wild-type) and DRP1-KO (knockout) H460 lung cancer cells and mouse embryonic fibroblasts (MEFs).
Mitochondrial staining confirmed that mdivi-1 treatment and DRP1 deficiency induced mitochondrial fusion. Surprisingly, metabolic isotope tracing found that mdivi-1 decreased mitochondrial oxidative metabolism in the lung cancer cell lines H460, A549 and the colon cancer cell line HCT116. [U-C]glucose tracing studies also showed that the TCA cycle intermediates had significantly lower enrichment in mdivi-1-treated cells. In comparison, DRP1-WT and DRP1-KO H460 cells had similar oxidative metabolism, which was decreased by mdivi-1 treatment. Furthermore, mdivi-1-mediated effects on oxidative metabolism were independent of mitochondrial fusion.
Our data suggest that, in cancer cells, mdivi-1, a putative inhibitor of DRP1, decreases oxidative metabolism to impair cell proliferation.
先前的研究表明，mdivi-1（线粒体分裂抑制剂），一种潜在的动力相关蛋白（DRP1）抑制剂，通过诱导线粒体融合和改变耗氧量来减少癌细胞增殖。然而，在癌细胞中，DRP1 抑制的代谢重编程仍不清楚。
为了更好地理解 DRP1 抑制的代谢效应，我们采用 [U-C] 葡萄糖同位素示踪法评估了几种癌细胞系、DRP1-WT（野生型）和 DRP1-KO（敲除）H460 肺癌细胞和小鼠胚胎成纤维细胞（MEFs）中 mdivi-1 的作用。
线粒体染色证实，mdivi-1 处理和 DRP1 缺失诱导了线粒体融合。令人惊讶的是，代谢同位素示踪发现，mdivi-1 降低了肺癌细胞系 H460、A549 和结肠癌细胞系 HCT116 的线粒体氧化代谢。[U-C] 葡萄糖示踪研究还表明，TCA 循环中间产物在 mdivi-1 处理的细胞中丰度显著降低。相比之下，DRP1-WT 和 DRP1-KO H460 细胞具有相似的氧化代谢，mdivi-1 处理后其氧化代谢降低。此外，mdivi-1 对氧化代谢的影响独立于线粒体融合。
我们的数据表明，在癌细胞中，DRP1 的一种潜在抑制剂 mdivi-1 通过降低氧化代谢来损害细胞增殖。
