FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion.
FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion.
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FUNDC2通过抑制MFN1介导的线粒体融合促进肝脏肿瘤发生
DOI：
10.1038/s41467-022-31187-6
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发表时间：
2022-06-17
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
线粒体产生 ATP 并在各种细胞活动中发挥调节作用。癌细胞通常表现出碎片化的线粒体。然而，潜在的机制仍然难以捉摸。在这里，我们报道了线粒体蛋白 FUN14 结构域包含 2 (FUNDC2) 在原发性小鼠肝脏肿瘤和大约 40% 的人类肝细胞癌 (HCC) 中转录上调。重要的是，FUNDC2 表达升高与患者生存呈负相关，其敲低可抑制小鼠肝脏肿瘤的发生。从机制上讲，FUNDC2 的氨基末端区域与线粒体融合蛋白 1 (MFN1) 的 GTPase 结构域相互作用，从而抑制其促进线粒体外膜融合的活性。因此，FUNDC2 的缺失会导致线粒体伸长、线粒体呼吸减少和细胞代谢重新编程。这些结果通过 FUNDC2 抑制 MFN1 确定了癌症中线粒体断裂的机制，并表明 FUNDC2 作为 HCC 的潜在治疗靶点。线粒体碎片是癌症的常见标志，但其原因和后果尚不清楚。作者证明，在肝细胞癌中，FUNDC2 升高可通过抑制 MFN1 导致线粒体断裂，而 FUNDC2 敲除可抑制小鼠肝脏肿瘤的发生。
Mitochondria generate ATP and play regulatory roles in various cellular activities. Cancer cells often exhibit fragmented mitochondria. However, the underlying mechanism remains elusive. Here we report that a mitochondrial protein FUN14 domain containing 2 (FUNDC2) is transcriptionally upregulated in primary mouse liver tumors, and in approximately 40% of human hepatocellular carcinoma (HCC). Importantly, elevated FUNDC2 expression inversely correlates with patient survival, and its knockdown inhibits liver tumorigenesis in mice. Mechanistically, the amino-terminal region of FUNDC2 interacts with the GTPase domain of mitofusin 1 (MFN1), thus inhibits its activity in promoting fusion of outer mitochondrial membrane. As a result, loss of FUNDC2 leads to mitochondrial elongation, decreased mitochondrial respiration, and reprogrammed cellular metabolism. These results identified a mechanism of mitochondrial fragmentation in cancer through MFN1 inhibition by FUNDC2, and suggested FUNDC2 as a potential therapeutic target of HCC. Fragmented mitochondria are a frequent hallmark of cancer, but the cause and consequence are less clear. The authors demonstrate that elevated FUNDC2 causes mitochondrial fragmentation through inhibition of MFN1 in hepatocellular carcinoma and that knockdown of FUNDC2 inhibits liver tumorigenesis in mice.
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影响因子：
64.8
作者：
Birsoy, Kivanc;Possemato, Richard;Lorbeer, Franziska K.;Bayraktar, Erol C.;Thiru, Prathapan;Yucel, Burcu;Wang, Tim;Chen, Walter W.;Clish, Clary B.;Sabatini, David M.
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Zhao B
影响因子：
82.9
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--
DOI：
10.1073/pnas.0703976104
发表时间：
2007-07-10
影响因子：
11.1
作者：
Brooks, Craig;Wei, Qingqing;Dong, Zheng
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Dong, Zheng
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影响因子：
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