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      The Mitochondrial Complex(I)ty of Cancer

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          Abstract

          Recent evidence highlights that the cancer cell energy requirements vary greatly from normal cells and that cancer cells exhibit different metabolic phenotypes with variable participation of both glycolysis and oxidative phosphorylation. NADH–ubiquinone oxidoreductase (Complex I) is the largest complex of the mitochondrial electron transport chain and contributes about 40% of the proton motive force required for mitochondrial ATP synthesis. In addition, Complex I plays an essential role in biosynthesis and redox control during proliferation, resistance to cell death, and metastasis of cancer cells. Although knowledge about the structure and assembly of Complex I is increasing, information about the role of Complex I subunits in tumorigenesis is scarce and contradictory. Several small molecule inhibitors of Complex I have been described as selective anticancer agents; however, pharmacologic and genetic interventions on Complex I have also shown pro-tumorigenic actions, involving different cellular signaling. Here, we discuss the role of Complex I in tumorigenesis, focusing on the specific participation of Complex I subunits in proliferation and metastasis of cancer cells.

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          Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

          William Wheaton, Samuel Weinberg, Robert B. Hamanaka … (2014)
          Recent epidemiological and laboratory-based studies suggest that the anti-diabetic drug metformin prevents cancer progression. How metformin diminishes tumor growth is not fully understood. In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I. DOI: http://dx.doi.org/10.7554/eLife.02242.001
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            Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria.

            César Cárdenas, Russell A Miller, Ian Smith … (2010)
            Mechanisms that regulate cellular metabolism are a fundamental requirement of all cells. Most eukaryotic cells rely on aerobic mitochondrial metabolism to generate ATP. Nevertheless, regulation of mitochondrial activity is incompletely understood. Here we identified an unexpected and essential role for constitutive InsP(3)R-mediated Ca(2+) release in maintaining cellular bioenergetics. Macroautophagy provides eukaryotes with an adaptive response to nutrient deprivation that prolongs survival. Constitutive InsP(3)R Ca(2+) signaling is required for macroautophagy suppression in cells in nutrient-replete media. In its absence, cells become metabolically compromised due to diminished mitochondrial Ca(2+) uptake. Mitochondrial uptake of InsP(3)R-released Ca(2+) is fundamentally required to provide optimal bioenergetics by providing sufficient reducing equivalents to support oxidative phosphorylation. Absence of this Ca(2+) transfer results in enhanced phosphorylation of pyruvate dehydrogenase and activation of AMPK, which activates prosurvival macroautophagy. Thus, constitutive InsP(3)R Ca(2+) release to mitochondria is an essential cellular process that is required for efficient mitochondrial respiration and maintenance of normal cell bioenergetics. Copyright 2010 Elsevier Inc. All rights reserved.
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              Function of mitochondrial Stat3 in cellular respiration.

              Joanna Wegrzyn, Ramesh Potla, Yong-Joon Chwae … (2009)
              Cytokines such as interleukin-6 induce tyrosine and serine phosphorylation of Stat3 that results in activation of Stat3-responsive genes. We provide evidence that Stat3 is present in the mitochondria of cultured cells and primary tissues, including the liver and heart. In Stat3(-/-) cells, the activities of complexes I and II of the electron transport chain (ETC) were significantly decreased. We identified Stat3 mutants that selectively restored the protein's function as a transcription factor or its functions within the ETC. In mice that do not express Stat3 in the heart, there were also selective defects in the activities of complexes I and II of the ETC. These data indicate that Stat3 is required for optimal function of the ETC, which may allow it to orchestrate responses to cellular homeostasis.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Oncol
                Journal ID (iso-abbrev): Front Oncol
                Journal ID (publisher-id): Front. Oncol.
                Title: Frontiers in Oncology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 2234-943X
                Publication date (Electronic): 08 June 2017
                Publication date Collection: 2017
                Volume: 7
                Electronic Location Identifier: 118
                Affiliations
                [1] 1Anatomy and Developmental Biology Program, Institute of Biomedical Sciences, University of Chile , Santiago, Chile
                [2] 2Geroscience Center for Brain Health and Metabolism , Santiago, Chile
                [3] 3Department of Neuroscience, Center for Neuroscience Research, Tufts School of Medicine , Boston, MA, United States
                [4] 4The Buck Institute for Research on Aging , Novato, CA, United States
                [5] 5Department of Chemistry and Biochemistry, University of California, Santa Barbara , Santa Barbara, CA, United States
                Author notes

                Edited by: Cristina Mammucari, University of Padua, Italy

                Reviewed by: Amadou K. S. Camara, Medical College of Wisconsin, United States; Eirini Lionaki, Foundation for Research and Technology Hellas, Greece

                *Correspondence: César Cárdenas, jcesar@ 123456u.uchile.cl

                Specialty section: This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology

                Article
                DOI: 10.3389/fonc.2017.00118
                PMC ID: 5462917
                PubMed ID: 28642839
                SO-VID: 95d5894a-d38f-4e8e-820f-8a1b54edc9f9
                Copyright © Copyright © 2017 Urra, Muñoz, Lovy and Cárdenas.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 22 February 2017
                Date accepted : 19 May 2017
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 106, Pages: 8, Words: 6784
                Funding
                Funded by: Fondo Nacional de Desarrollo Científico y Tecnológico 10.13039/501100002850
                Award ID: 1160332, 3170813
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: P30NS047243
                Categories
                Subject: Oncology
                Subject: Mini Review

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: electron transport chain,mitochondrial respiration,cancer cells,metastasis,anticancer agents
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: electron transport chain, mitochondrial respiration, cancer cells, metastasis, anticancer agents

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