Developmental and Tumor Angiogenesis Requires the Mitochondria-Shaping Protein Opa1
Developmental and Tumor Angiogenesis Requires the Mitochondria-Shaping Protein Opa1
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DOI：
10.1016/j.cmet.2020.04.007
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发表时间：
2020-05-05
期刊：
影响因子：
29
通讯作者：
Scorrano, Luca
中科院分区：
文献类型：
--
作者：
Herkenne, Stephanie;Ek, Olivier;Scorrano, Luca
虽然内皮细胞（EC）功能受到线粒体代谢的影响，但线粒体动力学在血管生成（从现有脉管系统形成新血管）中的作用尚不清楚。在这里，我们表明线粒体内膜线粒体融合蛋白视神经萎缩1（OPA1）是血管生成所必需的。为了响应血管生成刺激，OPA1 水平迅速增加，以限制激活 B 细胞 (NFkB) 信号传导的核因子 kappa-轻链增强子，最终允许血管生成基因表达和血管生成。内皮 Opa1 确实是发育和肿瘤血管生成所必需的 NFkB 依赖性途径所必需的，从而影响肿瘤生长和转移。一流的小分子特异性 OPA1 抑制剂证实 EC Opa1 可以通过药理学靶向抑制肿瘤生长。我们的数据表明 Opa1 是生理和肿瘤血管生成的重要组成部分。
While endothelial cell (EC) function is influenced by mitochondrialmetabolism, the role ofmitochondrial dynamics in angiogenesis, the formation of new blood vessels from existing vasculature, is unknown. Here we show that the inner mitochondrial membrane mitochondrial fusion protein optic atrophy 1 (OPA1) is required for angiogenesis. In response to angiogenic stimuli, OPA1 levels rapidly increase to limit nuclear factor kappa-light-chain-enhancer of activated B cell (NFkB) signaling, ultimately allowing angiogenic genes expression and angiogenesis. Endothelial Opa1 is indeed required in an NFkB-dependent pathway essential for developmental and tumor angiogenesis, impacting tumor growth and metastatization. A firstin-class small molecule-specific OPA1 inhibitor confirms that EC Opa1 can be pharmacologically targeted to curtail tumor growth. Our data identify Opa1 as a crucial component of physiological and tumor angiogenesis.