Mitochondrial complex IV defects induce metabolic and signaling perturbations that expose potential vulnerabilities in HCT116 cells
Mutations in genes encoding cytochrome c oxidase (mitochondrial complex IV) subunits and assembly factors [e.g., synthesis of cytochrome c oxidase 2 (SCO2)] are linked to severe metabolic syndromes. Notwithstanding that SCO2 is under transcriptional control of tumor suppressor p53, the role of mitoc...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-05-01
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| Series: | FEBS Open Bio |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/2211-5463.13398 |
| _version_ | 1811338232592334848 |
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| author | Oro Uchenunu Alexander V. Zhdanov Phillipe Hutton Predrag Jovanovic Ye Wang Dmitry E. Andreev Laura Hulea David J. Papadopoli Daina Avizonis Pavel V. Baranov Michael N. Pollak Dmitri B. Papkovsky Ivan Topisirovic |
| author_facet | Oro Uchenunu Alexander V. Zhdanov Phillipe Hutton Predrag Jovanovic Ye Wang Dmitry E. Andreev Laura Hulea David J. Papadopoli Daina Avizonis Pavel V. Baranov Michael N. Pollak Dmitri B. Papkovsky Ivan Topisirovic |
| author_sort | Oro Uchenunu |
| collection | DOAJ |
| description | Mutations in genes encoding cytochrome c oxidase (mitochondrial complex IV) subunits and assembly factors [e.g., synthesis of cytochrome c oxidase 2 (SCO2)] are linked to severe metabolic syndromes. Notwithstanding that SCO2 is under transcriptional control of tumor suppressor p53, the role of mitochondrial complex IV dysfunction in cancer metabolism remains obscure. Herein, we demonstrate that the loss of SCO2 in HCT116 colorectal cancer cells leads to significant metabolic and signaling perturbations. Specifically, abrogation of SCO2 increased NAD+ regenerating reactions and decreased glucose oxidation through citric acid cycle while enhancing pyruvate carboxylation. This was accompanied by a reduction in amino acid levels and the accumulation of lipid droplets. In addition, SCO2 loss resulted in hyperactivation of the insulin‐like growth factor 1 receptor (IGF1R)/AKT axis with paradoxical downregulation of mTOR signaling, which was accompanied by increased AMP‐activated kinase activity. Accordingly, abrogation of SCO2 expression appears to increase the sensitivity of cells to IGF1R and AKT, but not mTOR inhibitors. Finally, the loss of SCO2 was associated with reduced proliferation and enhanced migration of HCT116 cells. Collectively, herein we describe potential adaptive signaling and metabolic perturbations triggered by mitochondrial complex IV dysfunction. |
| first_indexed | 2024-04-13T18:07:53Z |
| format | Article |
| id | doaj.art-f8fde63c9e464bee9765b343a923087e |
| institution | Directory Open Access Journal |
| issn | 2211-5463 |
| language | English |
| last_indexed | 2024-04-13T18:07:53Z |
| publishDate | 2022-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | FEBS Open Bio |
| spelling | doaj.art-f8fde63c9e464bee9765b343a923087e2022-12-22T02:36:02ZengWileyFEBS Open Bio2211-54632022-05-0112595998210.1002/2211-5463.13398Mitochondrial complex IV defects induce metabolic and signaling perturbations that expose potential vulnerabilities in HCT116 cellsOro Uchenunu0Alexander V. Zhdanov1Phillipe Hutton2Predrag Jovanovic3Ye Wang4Dmitry E. Andreev5Laura Hulea6David J. Papadopoli7Daina Avizonis8Pavel V. Baranov9Michael N. Pollak10Dmitri B. Papkovsky11Ivan Topisirovic12Lady Davis Institute for Medical Research Jewish General Hospital Montréal CanadaSchool of Biochemistry and Cell Biology University College Cork IrelandLady Davis Institute for Medical Research Jewish General Hospital Montréal CanadaLady Davis Institute for Medical Research Jewish General Hospital Montréal CanadaLady Davis Institute for Medical Research Jewish General Hospital Montréal CanadaShemyakin‐Ovchinnikov Institute of Bioorganic Chemistry Moscow RussiaDépartement de Médecine Département de Biochimie et Médecine Moléculaire Université de Montréal Maisonneuve‐Rosemont Hospital Research Centre CanadaLady Davis Institute for Medical Research Jewish General Hospital Montréal CanadaGoodman Cancer Research Centre McGill University Montreal CanadaSchool of Biochemistry and Cell Biology University College Cork IrelandLady Davis Institute for Medical Research Jewish General Hospital Montréal CanadaSchool of Biochemistry and Cell Biology University College Cork IrelandLady Davis Institute for Medical Research Jewish General Hospital Montréal CanadaMutations in genes encoding cytochrome c oxidase (mitochondrial complex IV) subunits and assembly factors [e.g., synthesis of cytochrome c oxidase 2 (SCO2)] are linked to severe metabolic syndromes. Notwithstanding that SCO2 is under transcriptional control of tumor suppressor p53, the role of mitochondrial complex IV dysfunction in cancer metabolism remains obscure. Herein, we demonstrate that the loss of SCO2 in HCT116 colorectal cancer cells leads to significant metabolic and signaling perturbations. Specifically, abrogation of SCO2 increased NAD+ regenerating reactions and decreased glucose oxidation through citric acid cycle while enhancing pyruvate carboxylation. This was accompanied by a reduction in amino acid levels and the accumulation of lipid droplets. In addition, SCO2 loss resulted in hyperactivation of the insulin‐like growth factor 1 receptor (IGF1R)/AKT axis with paradoxical downregulation of mTOR signaling, which was accompanied by increased AMP‐activated kinase activity. Accordingly, abrogation of SCO2 expression appears to increase the sensitivity of cells to IGF1R and AKT, but not mTOR inhibitors. Finally, the loss of SCO2 was associated with reduced proliferation and enhanced migration of HCT116 cells. Collectively, herein we describe potential adaptive signaling and metabolic perturbations triggered by mitochondrial complex IV dysfunction.https://doi.org/10.1002/2211-5463.13398AKTAMPKcytochrome C oxidasemetabolismmitochondrial dysfunctionmTOR |
| spellingShingle | Oro Uchenunu Alexander V. Zhdanov Phillipe Hutton Predrag Jovanovic Ye Wang Dmitry E. Andreev Laura Hulea David J. Papadopoli Daina Avizonis Pavel V. Baranov Michael N. Pollak Dmitri B. Papkovsky Ivan Topisirovic Mitochondrial complex IV defects induce metabolic and signaling perturbations that expose potential vulnerabilities in HCT116 cells FEBS Open Bio AKT AMPK cytochrome C oxidase metabolism mitochondrial dysfunction mTOR |
| title | Mitochondrial complex IV defects induce metabolic and signaling perturbations that expose potential vulnerabilities in HCT116 cells |
| title_full | Mitochondrial complex IV defects induce metabolic and signaling perturbations that expose potential vulnerabilities in HCT116 cells |
| title_fullStr | Mitochondrial complex IV defects induce metabolic and signaling perturbations that expose potential vulnerabilities in HCT116 cells |
| title_full_unstemmed | Mitochondrial complex IV defects induce metabolic and signaling perturbations that expose potential vulnerabilities in HCT116 cells |
| title_short | Mitochondrial complex IV defects induce metabolic and signaling perturbations that expose potential vulnerabilities in HCT116 cells |
| title_sort | mitochondrial complex iv defects induce metabolic and signaling perturbations that expose potential vulnerabilities in hct116 cells |
| topic | AKT AMPK cytochrome C oxidase metabolism mitochondrial dysfunction mTOR |
| url | https://doi.org/10.1002/2211-5463.13398 |
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