FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion

• Published in: Nature communications Vol. 13; no. 1; pp. 3486 - 16
• Main Authors: Li, Shuaifeng, Han, Shixun, Zhang, Qi, Zhu, Yibing, Zhang, Haitao, Wang, Junli, Zhao, Yang, Zhao, Jianhui, Su, Lin, Li, Li, Zhou, Dawang, Ye, Cunqi, Feng, Xin-Hua, Liang, Tingbo, Zhao, Bin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.06.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 13/89; 13/95; 14; 14/19; 14/28; 38; 38/109; 631/67/1504/1610/4029; 631/67/2327; 631/80/642/333/1465; 64/60; Animals; Carcinogenesis - genetics; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Electron transport; Elongation; Fragmentation; GTP Phosphohydrolases - genetics; Hepatocellular carcinoma; Humanities and Social Sciences; Humans; Liver; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Membrane fusion; Mice; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membrane Transport Proteins - genetics; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Proteins - metabolism; multidisciplinary; Science; Science (multidisciplinary); Therapeutic targets; Tumorigenesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31187-6

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.