The Role of Mitochondrial H+-ATP Synthase in Cancer
Cancer cells reprogram energy metabolism by boosting aerobic glycolysis as a main pathway for the provision of metabolic energy and of precursors for anabolic purposes. Accordingly, the relative expression of the catalytic subunit of the mitochondrial H+-ATP synthase—the core hub of oxidative phosph...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fonc.2018.00053/full |
| _version_ | 1811209549157236736 |
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| author | Pau B. Esparza-Moltó José M. Cuezva |
| author_facet | Pau B. Esparza-Moltó José M. Cuezva |
| author_sort | Pau B. Esparza-Moltó |
| collection | DOAJ |
| description | Cancer cells reprogram energy metabolism by boosting aerobic glycolysis as a main pathway for the provision of metabolic energy and of precursors for anabolic purposes. Accordingly, the relative expression of the catalytic subunit of the mitochondrial H+-ATP synthase—the core hub of oxidative phosphorylation—is downregulated in human carcinomas when compared with its expression in normal tissues. Moreover, some prevalent carcinomas also upregulate the ATPase inhibitory factor 1 (IF1), which is the physiological inhibitor of the H+-ATP synthase. IF1 overexpression, both in cells in culture and in tissue-specific mouse models, is sufficient to reprogram energy metabolism to an enhanced glycolysis by limiting ATP production by the H+-ATP synthase. Furthermore, the IF1-mediated inhibition of the H+-ATP synthase promotes the production of mitochondrial ROS (mtROS). mtROS modulate signaling pathways favoring cellular proliferation and invasion, the activation of antioxidant defenses, resistance to cell death, and modulation of the tissue immune response, favoring the acquisition of several cancer traits. Consistently, IF1 expression is an independent marker of cancer prognosis. By contrast, inhibition of the H+-ATP synthase by α-ketoglutarate and the oncometabolite 2-hydroxyglutarate, reduces mTOR signaling, suppresses cancer cell growth, and contributes to lifespan extension in several model organisms. Hence, the H+-ATP synthase appears as a conserved hub in mitochondria-to-nucleus signaling controlling cell fate. Unraveling the molecular mechanisms responsible for IF1 upregulation in cancer and the signaling cascades that are modulated by the H+-ATP synthase are of utmost interest to decipher the metabolic and redox circuits contributing to cancer origin and progression. |
| first_indexed | 2024-04-12T04:40:23Z |
| format | Article |
| id | doaj.art-a0045ad6a082499c891022c692ea59d5 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T04:40:23Z |
| publishDate | 2018-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-a0045ad6a082499c891022c692ea59d52022-12-22T03:47:39ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2018-03-01810.3389/fonc.2018.00053351714The Role of Mitochondrial H+-ATP Synthase in CancerPau B. Esparza-Moltó0José M. Cuezva1Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Centro de Investigación Biomédica en Red de Enfermedades Raras CIBERER-ISCIII, Instituto de Investigación Hospital 12 de Octubre (i+12), Universidad Autónoma de Madrid, Madrid, SpainDepartamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Centro de Investigación Biomédica en Red de Enfermedades Raras CIBERER-ISCIII, Instituto de Investigación Hospital 12 de Octubre (i+12), Universidad Autónoma de Madrid, Madrid, SpainCancer cells reprogram energy metabolism by boosting aerobic glycolysis as a main pathway for the provision of metabolic energy and of precursors for anabolic purposes. Accordingly, the relative expression of the catalytic subunit of the mitochondrial H+-ATP synthase—the core hub of oxidative phosphorylation—is downregulated in human carcinomas when compared with its expression in normal tissues. Moreover, some prevalent carcinomas also upregulate the ATPase inhibitory factor 1 (IF1), which is the physiological inhibitor of the H+-ATP synthase. IF1 overexpression, both in cells in culture and in tissue-specific mouse models, is sufficient to reprogram energy metabolism to an enhanced glycolysis by limiting ATP production by the H+-ATP synthase. Furthermore, the IF1-mediated inhibition of the H+-ATP synthase promotes the production of mitochondrial ROS (mtROS). mtROS modulate signaling pathways favoring cellular proliferation and invasion, the activation of antioxidant defenses, resistance to cell death, and modulation of the tissue immune response, favoring the acquisition of several cancer traits. Consistently, IF1 expression is an independent marker of cancer prognosis. By contrast, inhibition of the H+-ATP synthase by α-ketoglutarate and the oncometabolite 2-hydroxyglutarate, reduces mTOR signaling, suppresses cancer cell growth, and contributes to lifespan extension in several model organisms. Hence, the H+-ATP synthase appears as a conserved hub in mitochondria-to-nucleus signaling controlling cell fate. Unraveling the molecular mechanisms responsible for IF1 upregulation in cancer and the signaling cascades that are modulated by the H+-ATP synthase are of utmost interest to decipher the metabolic and redox circuits contributing to cancer origin and progression.http://journal.frontiersin.org/article/10.3389/fonc.2018.00053/fulloxidative phosphorylationATPase inhibitory factor 1mitohormesismetabolic reprogramminghepatocarcinogenesisinflammation |
| spellingShingle | Pau B. Esparza-Moltó José M. Cuezva The Role of Mitochondrial H+-ATP Synthase in Cancer Frontiers in Oncology oxidative phosphorylation ATPase inhibitory factor 1 mitohormesis metabolic reprogramming hepatocarcinogenesis inflammation |
| title | The Role of Mitochondrial H+-ATP Synthase in Cancer |
| title_full | The Role of Mitochondrial H+-ATP Synthase in Cancer |
| title_fullStr | The Role of Mitochondrial H+-ATP Synthase in Cancer |
| title_full_unstemmed | The Role of Mitochondrial H+-ATP Synthase in Cancer |
| title_short | The Role of Mitochondrial H+-ATP Synthase in Cancer |
| title_sort | role of mitochondrial h atp synthase in cancer |
| topic | oxidative phosphorylation ATPase inhibitory factor 1 mitohormesis metabolic reprogramming hepatocarcinogenesis inflammation |
| url | http://journal.frontiersin.org/article/10.3389/fonc.2018.00053/full |
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