2. Academic Validation
  3. FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion

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

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. binzhao@zju.edu.cn.
  • 9 Cancer Center, Zhejiang University, Hangzhou, 310058, China. binzhao@zju.edu.cn.
  • 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. binzhao@zju.edu.cn.
  • 11 Shaoxing Institute, Zhejiang University, Shaoxing, 321000, China. binzhao@zju.edu.cn.
  • # 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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