FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion.

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. © 2022. The Author(s).

Citation

Shuaifeng Li, Shixun Han, Qi Zhang, Yibing Zhu, Haitao Zhang, Junli Wang, Yang Zhao, Jianhui Zhao, Lin Su, Li Li, Dawang Zhou, Cunqi Ye, Xin-Hua Feng, Tingbo Liang, Bin Zhao. FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion. Nature communications. 2022 Jun 17;13(1):3486

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PMID: 35710796

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