Mitochondrial Fusion Via OPA1 and MFN1 Supports Liver Tumor Cell Metabolism and Growth
Identifieur interne : 000480 ( Pmc/Curation ); précédent : 000479; suivant : 000481Mitochondrial 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.
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DOI: 10.3390/cells9010121
PubMed: 31947947
PubMed Central: 7017104
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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 type="wicri:Area/Pmc/Curation">000480</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000480</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">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></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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<front><journal-meta><journal-id journal-id-type="nlm-ta">Cells</journal-id><journal-id journal-id-type="iso-abbrev">Cells</journal-id><journal-id journal-id-type="publisher-id">cells</journal-id><journal-title-group><journal-title>Cells</journal-title></journal-title-group><issn pub-type="epub">2073-4409</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31947947</article-id><article-id pub-id-type="pmc">7017104</article-id><article-id pub-id-type="doi">10.3390/cells9010121</article-id><article-id pub-id-type="publisher-id">cells-09-00121</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Mitochondrial Fusion Via OPA1 and MFN1 Supports Liver Tumor Cell Metabolism and Growth</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Li</surname><given-names>Meng</given-names></name><xref ref-type="aff" rid="af1-cells-09-00121">1</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Ling</given-names></name><xref ref-type="aff" rid="af1-cells-09-00121">1</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Yijin</given-names></name><xref ref-type="aff" rid="af2-cells-09-00121">2</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Shaoshi</given-names></name><xref ref-type="aff" rid="af1-cells-09-00121">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Guoying</given-names></name><xref ref-type="aff" rid="af1-cells-09-00121">1</xref></contrib><contrib contrib-type="author"><name><surname>Lieshout</surname><given-names>Ruby</given-names></name><xref ref-type="aff" rid="af3-cells-09-00121">3</xref></contrib><contrib contrib-type="author"><name><surname>Ma</surname><given-names>Buyun</given-names></name><xref ref-type="aff" rid="af1-cells-09-00121">1</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Jiaye</given-names></name><xref ref-type="aff" rid="af1-cells-09-00121">1</xref></contrib><contrib contrib-type="author"><name><surname>Qu</surname><given-names>Changbo</given-names></name><xref ref-type="aff" rid="af1-cells-09-00121">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-9908-6673</contrib-id><name><surname>Verstegen</surname><given-names>Monique M. A.</given-names></name><xref ref-type="aff" rid="af3-cells-09-00121">3</xref></contrib><contrib contrib-type="author"><name><surname>Sprengers</surname><given-names>Dave</given-names></name><xref ref-type="aff" rid="af1-cells-09-00121">1</xref></contrib><contrib contrib-type="author"><name><surname>Kwekkeboom</surname><given-names>Jaap</given-names></name><xref ref-type="aff" rid="af1-cells-09-00121">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-0651-5334</contrib-id><name><surname>van der Laan</surname><given-names>Luc J. W.</given-names></name><xref ref-type="aff" rid="af3-cells-09-00121">3</xref></contrib><contrib contrib-type="author"><name><surname>Cao</surname><given-names>Wanlu</given-names></name><xref ref-type="aff" rid="af1-cells-09-00121">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-9112-6028</contrib-id><name><surname>Peppelenbosch</surname><given-names>Maikel P.</given-names></name><xref ref-type="aff" rid="af1-cells-09-00121">1</xref></contrib><contrib contrib-type="author"><name><surname>Pan</surname><given-names>Qiuwei</given-names></name><xref ref-type="aff" rid="af1-cells-09-00121">1</xref><xref rid="c1-cells-09-00121" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-cells-09-00121"><label>1</label>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.)</aff><aff id="af2-cells-09-00121"><label>2</label>Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing 100039, China;<email>yijinwang927015@163.com</email></aff><aff id="af3-cells-09-00121"><label>3</label>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.)</aff><author-notes><corresp id="c1-cells-09-00121"><label>*</label>Correspondence: <email>q.pan@erasmusmc.nl</email>; Tel.: +31-107037502</corresp></author-notes><pub-date pub-type="epub"><day>04</day><month>1</month><year>2020</year></pub-date><pub-date pub-type="collection"><month>1</month><year>2020</year></pub-date><volume>9</volume><issue>1</issue><elocation-id>121</elocation-id><history><date date-type="received"><day>20</day><month>12</month><year>2019</year></date><date date-type="accepted"><day>02</day><month>1</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 by the authors.</copyright-statement><copyright-year>2020</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><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></abstract><kwd-group><kwd>mitochondrial dynamics</kwd><kwd>liver cancer</kwd><kwd>OPA1</kwd><kwd>MFN1</kwd></kwd-group></article-meta></front><floats-group><fig id="cells-09-00121-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Activation of mitochondrial fusion in liver cancer. (<bold>A</bold>) Representative confocal images of mitochondria with VDAC1 staining in cryosection from paired tumor or adjacent liver tissues of two HCC patients. The white boxed regions were further magnified in the expanded images (left row). Scale bar = 5 µm (left row). Scale bar = 20 µm (right row). (<bold>B</bold>) Images of paired tissue were analyzed by ImageJ software. Mitochondrial volume per cell was determined by fluorescence area in pixels (Adjacent vs. Tumor: 80.29 ± 9.285 vs. 96.29 ± 7.24; n = 14 patients). (<bold>C</bold>) Fluorescent intensity represented the mean gray value of different images (Adjacent vs. Tumor: 100.3 ± 9.555 vs. 120.9 ± 11.18; n = 14 patients). (<bold>D</bold>) Integrated density was calculated by the product of area and mean gray value (Adjacent vs. Tumor: 1.245e+006 ± 260.203 vs. 1.848e + 006 ± 459.958; n = 14 patients). Histograms show means ± SEM with p value derived by two tailed paired Student’s <italic>t</italic> test. (<bold>E</bold>) The Oncomine microarray database (<uri xlink:href="https://www.oncomine.org">https://www.oncomine.org</uri>) was searched to analyze mRNA expression of OPA1 in HCC patients. In total, five cohorts of 423 HCC tumor tissues compared with 346 paired tumor-free tissues were identified. The expression level of OPA1 mRNA was demonstrated in five cohorts. (<bold>F</bold>) The Oncomine microarray database (<uri xlink:href="https://www.oncomine.org">https://www.oncomine.org</uri>) was searched to analyse mRNA expression of MFN1 in HCC patients. In total, five cohorts of 422 HCC tumor tissues compared with 346 paired tumor-free tissues were identified. The expression level of MFN1 mRNA was demonstrated in five cohorts. Histograms are mean ± SEM, with p values by Student’s <italic>t</italic> test.</p></caption><graphic xlink:href="cells-09-00121-g001"></graphic></fig><fig id="cells-09-00121-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Silencing of OPA1 or MFN1 inhibits mitochondrial fusion and the growth of CCA organoids. (<bold>A</bold>) Representative confocal images of mitochondria with TMRM staining in in vitro cultured organoids from two tumor tissue, one matched adjacent liver tissue and one donor liver tissue. The white boxed regions were further magnified in the expanded images (right row). Scale bar = 50 µm (left row). Scale bar = 10 µm (right row). (<bold>B</bold>) Images of tumor and non-tumor “normal” liver organoids were quantified (Normal vs. Tumor: 37.93 ± 10.62 vs. 83.5 ± 7.34; n = 6 images/sample). (<bold>C</bold>) CCA organoids were transduced with mock lentivirus (Ctr) or shOPA1/shMFN1 lentivirus (KD1 and KD2) respectively. Gene knockdown efficiency of OPA1 was quantified by Real-time PCR (n = 6). (<bold>D</bold>) Representative live cell confocal images of mitochondria with TMRM staining in CCA organoids with OPA1/MFN1 knockdown. The white boxed regions were further magnified in the expanded images (lower row). Scale bar = 20 µm (upper row). Scale bar = 5 µm (lower row). (<bold>E</bold>) Quantified measurements of mitochondrial length in control and KD cells of CCA organoids (n = 3 images/sample). (<bold>F</bold>) The Alamar Blue fluorescence level of CCA organoids was measured at Day 0/1/2/3 for cell viability and data at day 0 was set as control of each group (n = 3). Histograms show means ± SEM with p value derived by the Mann Whitney test.</p></caption><graphic xlink:href="cells-09-00121-g002"></graphic></fig><fig id="cells-09-00121-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Knockdown of OPA1 or MFN1 inhibits mitochondrial fusion. Inhibition of mitochondrial fusion attenuates cancer cell growth in vitro. (<bold>A</bold>) Real-time PCR analysis of OPA1 expression in Huh7/SNU449 shOPA1 cells and MFN1 expression in Huh7/SNU449 shMFN1 cells. Huh7/SNU449 shOPA1 cells were transfected with mock lentivirus (Ctr) and shOPA1 lentivirus (KD1 and KD2) respectively. Huh7/SNU449 shMFN1 cells were transfected with mock lentivirus (Ctr) and shMFN1 lentivirus (KD1 and KD2) respectively. Gene knockdown efficiency was quantified (n = 6). (<bold>B</bold>) Representative confocal images of mitochondria with TMRM staining in live cells with OPA1 and MFN1 knockdown respectively. The white boxed regions were further magnified in the expanded images (right row). Scale bar = 20 µm (left row). Scale bar = 5 µm (right row). (<bold>C</bold>) Quantified measurements of mitochondrial length in control and KD cells (n = 3 images/sample). (<bold>D</bold>) Representative images of colony formation assay of Huh7/SNU449 shOPA1 cells and shMFN1 cells. Cells were fixed and stained by Giemsa (n = 9). The number of colony forming units (CFU) was quantified by ImageJ software. Histograms show means ± SEM with p value by Mann Whitney test.</p></caption><graphic xlink:href="cells-09-00121-g003"></graphic></fig><fig id="cells-09-00121-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Mitochondrial fusion dysfunction inhibited tumor formation and growth in vivo. (<bold>A</bold>) Huh7 shOPA1 and control cells were injected subcutaneously into nude mice. Tumor size was measured at post-injection days 1/17/19/24/27 (n = 4 pairs). Huh7 shMFN1 and control cells were injected and tumor size was measured in the same way (n = 5 pairs). (<bold>B</bold>) Tumors were harvested from nude mice at day 27 and weighed. Histograms show means ± SEM with p value derived by the Mann Whitney test.</p></caption><graphic xlink:href="cells-09-00121-g004"></graphic></fig><fig id="cells-09-00121-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>Mitochondrial fusion dysfunction inhibited tumor growth through cell apoptosis induction (<bold>A</bold>,<bold>B</bold>) Apoptotic cells were quantified by flow cytometry using Annexin V and propidium iodide co-staining in Huh7 shOPA1 and Huh7 shMFN1 cells (n = 3). (<bold>C</bold>,<bold>D</bold>) Apoptotic cells were quantified by flow cytometry using Annexin V and propidium iodide co-staining in SNU449 shOPA1 and SNU449 shMFN1 cells (n = 3). Histograms show means ± SEM with p value derived by the Mann Whitney test.</p></caption><graphic xlink:href="cells-09-00121-g005"></graphic></fig><fig id="cells-09-00121-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>Inhibition of mitochondrial fusion affects cellular metabolism. (<bold>A</bold>) Volcano plot of statistical significance (<italic>p</italic> < 0.05) against fold change (ratio of KD/Ctr group), demonstrating the most significantly differentially expressed genes by genome-wide transcriptomic analysis between Ctr and shOPA1 Huh7 cells (n = 3). (<bold>B</bold>) KEGG pathway enrichment analysis within the complete set of differentially expressed genes (n = 3). (<bold>C</bold>) Heat map of color-coded expression levels of differentially expressed genes from metabolism pathway (two way ANOVA) (n = 3). (<bold>D</bold>) The ROS product level of SNU449 cells with OPA1/MFN1 downregulation showed increased ROS level compared with control group (n = 6). (<bold>E</bold>) The ROS product level of CCA organoids with OPA1/MFN1 downregulation showed increased ROS level compared with control group (n = 6). Histograms are mean ± SEM, with p values by Mann Whitney test.</p></caption><graphic xlink:href="cells-09-00121-g006"></graphic></fig><fig id="cells-09-00121-f007" orientation="portrait" position="float"><label>Figure 7</label><caption><p>Inhibition of mitochondrial fusion affects Oxygen Consumption Rate and ATP production. (<bold>A</bold>) Real-time analysis of basal Oxygen Consumption Rate (OCR) in Huh7 shOPA1 and shMFN1 cells (n = 3). (<bold>B</bold>) ATP production of Huh7 cells with OPA1/MFN1 downregulation was reduced compared with control group (n = 6). (<bold>C</bold>) Real-time analysis of basal OCR in CCA organoids with shOPA1 and shMFN1 (n = 3). (<bold>D</bold>) ATP production of CCA tumor organoids with OPA1/MFN1 downregulation was reduced compared with control group (n = 6). Histograms show means ± SEM with p value derived by the Mann Whitney test.</p></caption><graphic xlink:href="cells-09-00121-g007"></graphic></fig><table-wrap id="cells-09-00121-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">cells-09-00121-t001_Table 1</object-id><label>Table 1</label><caption><p>Patient Characteristics.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Characteristics</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">HCC Patient (n = 13)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">CCA Patient (n = 1)</th></tr></thead><tbody><tr><td colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Age at surgery (years)</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mean ± SD</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">64.9 ± 13.4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">60</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Median (range)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">70 (37–79)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td></tr><tr><td colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">sex (%)</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8 (62)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 (100)</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Female</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5 (38)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td></tr><tr><td colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Etiology (%)</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Unknown liver disease</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">6 (46)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Alcohol abuse</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 (8)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 (100)</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chronic HBV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3 (23)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hemochromatosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 (8)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hemochromatosis and alcohol abuse</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2 (15)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cirrhosis (%)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Yes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2 (15)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">No</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">11 (85)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 (100)</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Tumor differentiation (%)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Well</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 (8)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Moderate </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">9 (69)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Poor </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2 (15)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Unknown</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 (8)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 (100)</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Vascular invasion (%)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Micro-invasion</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">6 (46)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Vaso-invasion</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2 (15)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Severe vaso-invasion</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2 (15)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 (100)</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">No</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3 (23)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td></tr><tr><td colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">AFP (pre-operative) (µg/L)</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mean ± SD</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4076.2 ± 12607.2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3.8</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Median (range)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">16 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