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微调 Drp1 驱动的线粒体分裂抑制可激活“干细胞/祖细胞样状态”，以支持肿瘤转化。

Fine-tuned repression of Drp1-driven mitochondrial fission primes a 'stem/progenitor-like state' to support neoplastic transformation.

机构信息

Department of Genetics, University of Alabama at Birmingham, Birmingham, United States.

Departments of Pathology, University of Alabama at Birmingham, Birmingham, United States.

出版信息

Elife. 2021 Sep 21;10:e68394. doi: 10.7554/eLife.68394.

DOI:10.7554/eLife.68394
PMID:34545812
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8497058/
Abstract

Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. Also, mitochondrial fission and its opposing process of mitochondrial fusion are emerging as crucial regulators of stemness. Intriguingly, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Using our newly derived carcinogen transformed human cell model, we demonstrate that fine-tuned Drp1 repression primes a slow cycling 'stem/progenitor-like state', which is characterized by small networks of fused mitochondria and a gene-expression profile with elevated functional stem/progenitor markers (Krt15, Sox2 etc) and their regulators (Cyclin E). Fine tuning Drp1 protein by reducing its activating phosphorylation sustains the neoplastic stem/progenitor cell markers. Whereas, fine-tuned reduction of Drp1 protein maintains the characteristic mitochondrial shape and gene-expression of the primed 'stem/progenitor-like state' to accelerate neoplastic transformation, and more complete reduction of Drp1 protein prevents it. Therefore, our data highlights a 'goldilocks' level of Drp1 repression supporting stem/progenitor state dependent neoplastic transformation.

摘要

线粒体裂变的主调控因子 Drp1 的基因敲除可预防肿瘤转化。此外，线粒体裂变及其相反的线粒体融合过程正在成为干细胞特性的关键调节因子。有趣的是，维持受抑制的线粒体裂变的干细胞/祖细胞已为自我更新和增殖做好准备。使用我们新获得的致癌物转化的人类细胞模型，我们证明了精细调控的 Drp1 抑制可引发缓慢循环的“干细胞/祖细胞样状态”，其特征是融合线粒体的小网络和具有升高的功能性干细胞/祖细胞标志物（Krt15、Sox2 等）及其调节剂（Cyclin E）的基因表达谱。通过减少其激活磷酸化来精细调节 Drp1 蛋白可维持肿瘤干细胞/祖细胞标志物。然而，精细调节的 Drp1 蛋白减少可维持“干细胞/祖细胞样状态”的特征性线粒体形状和基因表达，以加速肿瘤转化，而更完全的 Drp1 蛋白减少可阻止肿瘤转化。因此，我们的数据强调了 Drp1 抑制的“金发姑娘”水平支持干细胞/祖细胞状态依赖性肿瘤转化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/d09062dedfaf/elife-68394-fig5-figsupp2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/037e56735098/elife-68394-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/f731bc23aa14/elife-68394-fig3-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/072bf963b97b/elife-68394-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/d09062dedfaf/elife-68394-fig5-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/8360162af75b/elife-68394-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/9e34adf6b69f/elife-68394-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/0c3d0e2a1cb0/elife-68394-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/1ee86cdb857b/elife-68394-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/037e56735098/elife-68394-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/f731bc23aa14/elife-68394-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/cf2960bcc3cf/elife-68394-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/756431f6201a/elife-68394-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/50966967458b/elife-68394-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/072bf963b97b/elife-68394-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3d2/8497058/d09062dedfaf/elife-68394-fig5-figsupp2.jpg

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