FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion
© 2022. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
Nature communications - 13(2022), 1 vom: 17. Juni, Seite 3486 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Shuaifeng [VerfasserIn] |
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| Links: |
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| Themen: |
EC 3.6.1.- |
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| Anmerkungen: |
Date Completed 20.06.2022 Date Revised 13.11.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-022-31187-6 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM34232148X |
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| 520 | |a © 2022. The Author(s). | ||
| 520 | |a 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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| 700 | 1 | |a Han, Shixun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Yibing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Haitao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Junli |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jianhui |e verfasserin |4 aut | |
| 700 | 1 | |a Su, Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Dawang |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Cunqi |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Xin-Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Tingbo |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Bin |e verfasserin |4 aut | |
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