FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion

  • Nat Commun. 2022 Jun 17;13(1):3486. doi: 10.1038/s41467-022-31187-6.
Shuaifeng Li   #  1  2 ,  Shixun Han   #  1  2 ,  Qi Zhang  3 ,  Yibing Zhu  1 ,  Haitao Zhang  1  2 ,  Junli Wang  3 ,  Yang Zhao  1  2 ,  Jianhui Zhao  3 ,  Lin Su  4 ,  Li Li  5 ,  Dawang Zhou  6 ,  Cunqi Ye  1 ,  Xin-Hua Feng  1  2  7 ,  Tingbo Liang  3 ,  Bin Zhao  8  9  10  11
Affiliations
  • 1. The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China.
  • 2. Cancer Center, Zhejiang University, Hangzhou, 310058, China.
  • 3. Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
  • 4. Department of Ultrasound Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.
  • 5. Institute of Aging Research, Hangzhou Normal University, Hangzhou, 311121, China.
  • 6. School of Life Sciences, Xiamen University, Xiamen, 361102, China.
  • 7. Shaoxing Institute, Zhejiang University, Shaoxing, 321000, China.
  • 8. The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China. [email protected].
  • 9. Cancer Center, Zhejiang University, Hangzhou, 310058, China. [email protected].
  • 10. Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China. [email protected].
  • 11. Shaoxing Institute, Zhejiang University, Shaoxing, 321000, China. [email protected].
  • # Contributed equally.
PMID: 35710796 DOI: 10.1038/s41467-022-31187-6
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.

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