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      Mitochondrial composition and function under the control of hypoxia

      review-article
      Author(s): a , a , b , *
      Publication date (Electronic):
      Journal: Redox Biology
      Publisher: Elsevier
      Keywords: Mitochondria, ROS, Hypoxia, HIF, Respiratory chain

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          Abstract

          Hypoxia triggers several mechanisms to adapt cells to a low oxygen environment. Mitochondria are major consumers of oxygen and a potential source of reactive oxygen species (ROS). In response to hypoxia they exchange or modify distinct subunits of the respiratory chain and adjust their metabolism, especially lowering the citric acid cycle. Intermediates of the citric acid cycle participate in regulating hypoxia inducible factors (HIF), the key mediators of adaptation to hypoxia. Here we summarize how hypoxia conditions mitochondria with consequences for ROS-production and the HIF-pathway.

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          Highlights

          • •

            Hypoxia provokes changes in mitochondrial morphology, metabolism, and respiration.

          • •

            Hypoxia calls forth changes in redox signaling.

          • •

            HIF-signaling is linked to mitochondrial metabolism and ROS formation.

          • •

            Hypoxia adjusts ETC complex formation, activity, respiration, and ROS formation.

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          Most cited references67

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          Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia.

          Huafeng Zhang, Marta Bosch-Marce, Larissa Shimoda … (2008)
          Autophagy is a process by which cytoplasmic organelles can be catabolized either to remove defective structures or as a means of providing macromolecules for energy generation under conditions of nutrient starvation. In this study we demonstrate that mitochondrial autophagy is induced by hypoxia, that this process requires the hypoxia-dependent factor-1-dependent expression of BNIP3 and the constitutive expression of Beclin-1 and Atg5, and that in cells subjected to prolonged hypoxia, mitochondrial autophagy is an adaptive metabolic response which is necessary to prevent increased levels of reactive oxygen species and cell death.
          Article 0 comments Cited 549 times – based on 0 reviews     Review now
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            Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases.

            Hideaki Kamata, Shi-Ichi Honda, Shin Maeda … (2005)
            TNFalpha is a pleiotropic cytokine that induces either cell proliferation or cell death. Inhibition of NF-kappaB activation increases susceptibility to TNFalpha-induced death, concurrent with sustained JNK activation, an important contributor to the death response. Sustained JNK activation in NF-kappaB-deficient cells was suggested to depend on reactive oxygen species (ROS), but how ROS affect JNK activation was unclear. We now show that TNFalpha-induced ROS, whose accumulation is suppressed by mitochondrial superoxide dismutase, cause oxidation and inhibition of JNK-inactivating phosphatases by converting their catalytic cysteine to sulfenic acid. This results in sustained JNK activation, which is required for cytochrome c release and caspase 3 cleavage, as well as necrotic cell death. Treatment of cells or experimental animals with an antioxidant prevents H(2)O(2) accumulation, JNK phosphatase oxidation, sustained JNK activity, and both forms of cell death. Antioxidant treatment also prevents TNFalpha-mediated fulminant liver failure without affecting liver regeneration.
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              Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability.

              David R Wise, Patrick Ward, Jessica Shay … (2011)
              Citrate is a critical metabolite required to support both mitochondrial bioenergetics and cytosolic macromolecular synthesis. When cells proliferate under normoxic conditions, glucose provides the acetyl-CoA that condenses with oxaloacetate to support citrate production. Tricarboxylic acid (TCA) cycle anaplerosis is maintained primarily by glutamine. Here we report that some hypoxic cells are able to maintain cell proliferation despite a profound reduction in glucose-dependent citrate production. In these hypoxic cells, glutamine becomes a major source of citrate. Glutamine-derived α-ketoglutarate is reductively carboxylated by the NADPH-linked mitochondrial isocitrate dehydrogenase (IDH2) to form isocitrate, which can then be isomerized to citrate. The increased IDH2-dependent carboxylation of glutamine-derived α-ketoglutarate in hypoxia is associated with a concomitant increased synthesis of 2-hydroxyglutarate (2HG) in cells with wild-type IDH1 and IDH2. When either starved of glutamine or rendered IDH2-deficient by RNAi, hypoxic cells are unable to proliferate. The reductive carboxylation of glutamine is part of the metabolic reprogramming associated with hypoxia-inducible factor 1 (HIF1), as constitutive activation of HIF1 recapitulates the preferential reductive metabolism of glutamine-derived α-ketoglutarate even in normoxic conditions. These data support a role for glutamine carboxylation in maintaining citrate synthesis and cell growth under hypoxic conditions.
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                Author and article information

                Contributors
                Bernhard Brüne
                Journal
                Journal ID (nlm-ta): Redox Biol
                Journal ID (iso-abbrev): Redox Biol
                Title: Redox Biology
                Publisher: Elsevier
                ISSN (Electronic): 2213-2317
                Publication date PMC-release: 24 February 2017
                Publication date Collection: August 2017
                Publication date (Electronic): 24 February 2017
                Volume: 12
                Pages: 208-215
                Affiliations
                [a ]Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany
                [b ]Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology, 60596 Frankfurt, Germany
                Author notes
                [* ]Corresponding author at: Goethe-University Frankfurt, Faculty of Medicine, Institute of Biochemistry I, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. b.bruene@ 123456biochem.uni-frankfurt.de
                Article
                Publisher ID: S2213-2317(17)30004-6
                DOI: 10.1016/j.redox.2017.02.012
                PMC ID: 5333533
                PubMed ID: 28259101
                SO-VID: 78e38db8-5b74-4932-bea0-5d26c7309cc2
                Copyright © © 2017 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 3 January 2017
                Date revision received : 31 January 2017
                Date accepted : 18 February 2017
                Categories
                Subject: Review Article

                Keywords: mitochondria,ros,hypoxia,hif,respiratory chain
                Data availability:
                Keywords: mitochondria, ros, hypoxia, hif, respiratory chain

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