Mitochondrial Fusion Via OPA1 and MFN1 Supports Liver Tumor Cell Metabolism and Growth
Identifieur interne : 000107 ( Main/Exploration ); précédent : 000106; suivant : 000108Mitochondrial Fusion Via OPA1 and MFN1 Supports Liver Tumor Cell Metabolism and Growth
Auteurs : Meng Li ; Ling Wang ; Yijin Wang ; Shaoshi Zhang ; Guoying Zhou ; Ruby Lieshout ; Buyun Ma ; Jiaye Liu ; Changbo Qu ; Monique M. A. Verstegen ; Dave Sprengers ; Jaap Kwekkeboom ; Luc J. W. Van Der Laan ; Wanlu Cao ; Maikel P. Peppelenbosch ; Qiuwei PanSource :
- Cells [ 2073-4409 ] ; 2020.
Abstract
Metabolic reprogramming universally occurs in cancer. Mitochondria act as the hubs of bioenergetics and metabolism. The morphodynamics of mitochondria, comprised of fusion and fission processes, are closely associated with mitochondrial functions and are often dysregulated in cancer. In this study, we aim to investigate the mitochondrial morphodynamics and its functional consequences in human liver cancer. We observed excessive activation of mitochondrial fusion in tumor tissues from hepatocellular carcinoma (HCC) patients and in vitro cultured tumor organoids from cholangiocarcinoma (CCA). The knockdown of the fusion regulator genes, OPA1 (Optic atrophy 1) or MFN1 (Mitofusin 1), inhibited the fusion process in HCC cell lines and CCA tumor organoids. This resulted in inhibition of cell growth in vitro and tumor formation in vivo, after tumor cell engraftment in mice. This inhibitory effect is associated with the induction of cell apoptosis, but not related to cell cycle arrest. Genome-wide transcriptomic profiling revealed that the inhibition of fusion predominately affected cellular metabolic pathways. This was further confirmed by the blocking of mitochondrial fusion which attenuated oxygen consumption and cellular ATP production of tumor cells. In conclusion, increased mitochondrial fusion in liver cancer alters metabolism and fuels tumor cell growth.
Url:
DOI: 10.3390/cells9010121
PubMed: 31947947
PubMed Central: 7017104
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mitochondrial Fusion Via OPA1 and MFN1 Supports Liver Tumor Cell Metabolism and Growth</title><author><name sortKey="Li, Meng" sort="Li, Meng" uniqKey="Li M" first="Meng" last="Li">Meng Li</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Wang, Ling" sort="Wang, Ling" uniqKey="Wang L" first="Ling" last="Wang">Ling Wang</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Wang, Yijin" sort="Wang, Yijin" uniqKey="Wang Y" first="Yijin" last="Wang">Yijin Wang</name><affiliation><nlm:aff id="af2-cells-09-00121">Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing 100039, China;<email>yijinwang927015@163.com</email></nlm:aff></affiliation></author><author><name sortKey="Zhang, Shaoshi" sort="Zhang, Shaoshi" uniqKey="Zhang S" first="Shaoshi" last="Zhang">Shaoshi Zhang</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Zhou, Guoying" sort="Zhou, Guoying" uniqKey="Zhou G" first="Guoying" last="Zhou">Guoying Zhou</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Lieshout, Ruby" sort="Lieshout, Ruby" uniqKey="Lieshout R" first="Ruby" last="Lieshout">Ruby Lieshout</name><affiliation><nlm:aff id="af3-cells-09-00121">Department of Surgery, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>r.lieshout@erasmusmc.nl</email> (R.L.);<email>m.verstegen@erasmusmc.nl</email> (M.M.A.V.);<email>l.vanderlaan@erasmusmc.nl</email> (L.J.W.v.d.L.)</nlm:aff></affiliation></author><author><name sortKey="Ma, Buyun" sort="Ma, Buyun" uniqKey="Ma B" first="Buyun" last="Ma">Buyun Ma</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Liu, Jiaye" sort="Liu, Jiaye" uniqKey="Liu J" first="Jiaye" last="Liu">Jiaye Liu</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Qu, Changbo" sort="Qu, Changbo" uniqKey="Qu C" first="Changbo" last="Qu">Changbo Qu</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Verstegen, Monique M A" sort="Verstegen, Monique M A" uniqKey="Verstegen M" first="Monique M. A." last="Verstegen">Monique M. A. Verstegen</name><affiliation><nlm:aff id="af3-cells-09-00121">Department of Surgery, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>r.lieshout@erasmusmc.nl</email> (R.L.);<email>m.verstegen@erasmusmc.nl</email> (M.M.A.V.);<email>l.vanderlaan@erasmusmc.nl</email> (L.J.W.v.d.L.)</nlm:aff></affiliation></author><author><name sortKey="Sprengers, Dave" sort="Sprengers, Dave" uniqKey="Sprengers D" first="Dave" last="Sprengers">Dave Sprengers</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Kwekkeboom, Jaap" sort="Kwekkeboom, Jaap" uniqKey="Kwekkeboom J" first="Jaap" last="Kwekkeboom">Jaap Kwekkeboom</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Van Der Laan, Luc J W" sort="Van Der Laan, Luc J W" uniqKey="Van Der Laan L" first="Luc J. W." last="Van Der Laan">Luc J. W. Van Der Laan</name><affiliation><nlm:aff id="af3-cells-09-00121">Department of Surgery, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>r.lieshout@erasmusmc.nl</email> (R.L.);<email>m.verstegen@erasmusmc.nl</email> (M.M.A.V.);<email>l.vanderlaan@erasmusmc.nl</email> (L.J.W.v.d.L.)</nlm:aff></affiliation></author><author><name sortKey="Cao, Wanlu" sort="Cao, Wanlu" uniqKey="Cao W" first="Wanlu" last="Cao">Wanlu Cao</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Peppelenbosch, Maikel P" sort="Peppelenbosch, Maikel P" uniqKey="Peppelenbosch M" first="Maikel P." last="Peppelenbosch">Maikel P. Peppelenbosch</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Pan, Qiuwei" sort="Pan, Qiuwei" uniqKey="Pan Q" first="Qiuwei" last="Pan">Qiuwei Pan</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31947947</idno><idno type="pmc">7017104</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017104</idno><idno type="RBID">PMC:7017104</idno><idno type="doi">10.3390/cells9010121</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000480</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000480</idno><idno 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Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Wang, Ling" sort="Wang, Ling" uniqKey="Wang L" first="Ling" last="Wang">Ling Wang</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Wang, Yijin" sort="Wang, Yijin" uniqKey="Wang Y" first="Yijin" last="Wang">Yijin Wang</name><affiliation><nlm:aff id="af2-cells-09-00121">Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing 100039, China;<email>yijinwang927015@163.com</email></nlm:aff></affiliation></author><author><name sortKey="Zhang, Shaoshi" sort="Zhang, Shaoshi" uniqKey="Zhang S" first="Shaoshi" last="Zhang">Shaoshi Zhang</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Zhou, Guoying" sort="Zhou, Guoying" uniqKey="Zhou G" first="Guoying" last="Zhou">Guoying Zhou</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Lieshout, Ruby" sort="Lieshout, Ruby" uniqKey="Lieshout R" first="Ruby" last="Lieshout">Ruby Lieshout</name><affiliation><nlm:aff id="af3-cells-09-00121">Department of Surgery, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>r.lieshout@erasmusmc.nl</email> (R.L.);<email>m.verstegen@erasmusmc.nl</email> (M.M.A.V.);<email>l.vanderlaan@erasmusmc.nl</email> (L.J.W.v.d.L.)</nlm:aff></affiliation></author><author><name sortKey="Ma, Buyun" sort="Ma, Buyun" uniqKey="Ma B" first="Buyun" last="Ma">Buyun Ma</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Liu, Jiaye" sort="Liu, Jiaye" uniqKey="Liu J" first="Jiaye" last="Liu">Jiaye Liu</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Qu, Changbo" sort="Qu, Changbo" uniqKey="Qu C" first="Changbo" last="Qu">Changbo Qu</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Verstegen, Monique M A" sort="Verstegen, Monique M A" uniqKey="Verstegen M" first="Monique M. A." last="Verstegen">Monique M. A. Verstegen</name><affiliation><nlm:aff id="af3-cells-09-00121">Department of Surgery, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>r.lieshout@erasmusmc.nl</email> (R.L.);<email>m.verstegen@erasmusmc.nl</email> (M.M.A.V.);<email>l.vanderlaan@erasmusmc.nl</email> (L.J.W.v.d.L.)</nlm:aff></affiliation></author><author><name sortKey="Sprengers, Dave" sort="Sprengers, Dave" uniqKey="Sprengers D" first="Dave" last="Sprengers">Dave Sprengers</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Kwekkeboom, Jaap" sort="Kwekkeboom, Jaap" uniqKey="Kwekkeboom J" first="Jaap" last="Kwekkeboom">Jaap Kwekkeboom</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Van Der Laan, Luc J W" sort="Van Der Laan, Luc J W" uniqKey="Van Der Laan L" first="Luc J. W." last="Van Der Laan">Luc J. W. Van Der Laan</name><affiliation><nlm:aff id="af3-cells-09-00121">Department of Surgery, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>r.lieshout@erasmusmc.nl</email> (R.L.);<email>m.verstegen@erasmusmc.nl</email> (M.M.A.V.);<email>l.vanderlaan@erasmusmc.nl</email> (L.J.W.v.d.L.)</nlm:aff></affiliation></author><author><name sortKey="Cao, Wanlu" sort="Cao, Wanlu" uniqKey="Cao W" first="Wanlu" last="Cao">Wanlu Cao</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Peppelenbosch, Maikel P" sort="Peppelenbosch, Maikel P" uniqKey="Peppelenbosch M" first="Maikel P." last="Peppelenbosch">Maikel P. Peppelenbosch</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author><author><name sortKey="Pan, Qiuwei" sort="Pan, Qiuwei" uniqKey="Pan Q" first="Qiuwei" last="Pan">Qiuwei Pan</name><affiliation><nlm:aff id="af1-cells-09-00121">Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015 CE Rotterdam, The Netherlands;<email>l.li.1@erasmusmc.nl</email> (M.L.);<email>l.wang.1@erasmusmc.nl</email> (L.W.);<email>s.zhang@erasmusmc.nl</email> (S.Z.);<email>g.zhou@erasmusmc.nl</email> (G.Z.);<email>b.ma@erasmusmc.nl</email> (B.M.);<email>j.liu.2@erasmusmc.nl</email> (J.L.);<email>c.qu@erasmusmc.nl</email> (C.Q.);<email>d.sprengers@erasmusmc.nl</email> (D.S.);<email>j.kwekkeboom@erasmusmc.nl</email> (J.K.);<email>w.cao@erasmusmc.nl</email> (W.C.);<email>m.peppelenbosch@erasmusmc.nl</email> (M.P.P.)</nlm:aff></affiliation></author></analytic><series><title level="j">Cells</title><idno type="eISSN">2073-4409</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Metabolic reprogramming universally occurs in cancer. Mitochondria act as the hubs of bioenergetics and metabolism. The morphodynamics of mitochondria, comprised of fusion and fission processes, are closely associated with mitochondrial functions and are often dysregulated in cancer. In this study, we aim to investigate the mitochondrial morphodynamics and its functional consequences in human liver cancer. We observed excessive activation of mitochondrial fusion in tumor tissues from hepatocellular carcinoma (HCC) patients and in vitro cultured tumor organoids from cholangiocarcinoma (CCA). The knockdown of the fusion regulator genes, OPA1 (Optic atrophy 1) or MFN1 (Mitofusin 1), inhibited the fusion process in HCC cell lines and CCA tumor organoids. This resulted in inhibition of cell growth in vitro and tumor formation in vivo, after tumor cell engraftment in mice. This inhibitory effect is associated with the induction of cell apoptosis, but not related to cell cycle arrest. Genome-wide transcriptomic profiling revealed that the inhibition of fusion predominately affected cellular metabolic pathways. This was further confirmed by the blocking of mitochondrial fusion which attenuated oxygen consumption and cellular ATP production of tumor cells. In conclusion, increased mitochondrial fusion in liver cancer alters metabolism and fuels tumor cell growth.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bray, F" uniqKey="Bray F">F. Bray</name></author><author><name sortKey="Ferlay, J" uniqKey="Ferlay J">J. Ferlay</name></author><author><name sortKey="Soerjomataram, I" uniqKey="Soerjomataram I">I. Soerjomataram</name></author><author><name sortKey="Siegel, R L" uniqKey="Siegel R">R.L. Siegel</name></author><author><name sortKey="Torre, L A" uniqKey="Torre L">L.A. Torre</name></author><author><name sortKey="Jemal, A" uniqKey="Jemal A">A. 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