FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion

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 and Bin Zhao ()
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Shuaifeng Li: Zhejiang University
Shixun Han: Zhejiang University
Qi Zhang: Zhejiang University
Yibing Zhu: Zhejiang University
Haitao Zhang: Zhejiang University
Junli Wang: Zhejiang University
Yang Zhao: Zhejiang University
Jianhui Zhao: Zhejiang University
Lin Su: The University of Hong Kong-Shenzhen Hospital
Li Li: Hangzhou Normal University
Dawang Zhou: Xiamen University
Cunqi Ye: Zhejiang University
Xin-Hua Feng: Zhejiang University
Tingbo Liang: Zhejiang University
Bin Zhao: Zhejiang University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-31187-6

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