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      Mitochondria and Energetic Depression in Cell Pathophysiology

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          Abstract

          Mitochondrial dysfunction is a hallmark of almost all diseases. Acquired or inherited mutations of the mitochondrial genome DNA may give rise to mitochondrial diseases. Another class of disorders, in which mitochondrial impairments are initiated by extramitochondrial factors, includes neurodegenerative diseases and syndromes resulting from typical pathological processes, such as hypoxia/ischemia, inflammation, intoxications, and carcinogenesis. Both classes of diseases lead to cellular energetic depression (CED), which is characterized by decreased cytosolic phosphorylation potential that suppresses the cell’s ability to do work and control the intracellular Ca 2+ homeostasis and its redox state. If progressing, CED leads to cell death, whose type is linked to the functional status of the mitochondria. In the case of limited deterioration, when some amounts of ATP can still be generated due to oxidative phosphorylation (OXPHOS), mitochondria launch the apoptotic cell death program by release of cytochrome c. Following pronounced CED, cytoplasmic ATP levels fall below the thresholds required for processing the ATP-dependent apoptotic cascade and the cell dies from necrosis. Both types of death can be grouped together as a mitochondrial cell death (MCD). However, there exist multiple adaptive reactions aimed at protecting cells against CED. In this context, a metabolic shift characterized by suppression of OXPHOS combined with activation of aerobic glycolysis as the main pathway for ATP synthesis (Warburg effect) is of central importance. Whereas this type of adaptation is sufficiently effective to avoid CED and to control the cellular redox state, thereby ensuring the cell survival, it also favors the avoidance of apoptotic cell death. This scenario may underlie uncontrolled cellular proliferation and growth, eventually resulting in carcinogenesis.

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          Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation.

          Complex interplay between T helper (Th) cells and macrophages contributes to the formation and progression of atherosclerotic plaques. While Th1 cytokines promote inflammatory activation of lesion macrophages, Th2 cytokines attenuate macrophage-mediated inflammation and enhance their repair functions. In spite of its biologic importance, the biochemical and molecular basis of how Th2 cytokines promote maturation of anti-inflammatory macrophages is not understood. We show here that in response to interleukin-4 (IL-4), signal transducer and activator of transcription 6 (STAT6) and PPARgamma-coactivator-1beta (PGC-1beta) induce macrophage programs for fatty acid oxidation and mitochondrial biogenesis. Transgenic expression of PGC-1beta primes macrophages for alternative activation and strongly inhibits proinflammatory cytokine production, whereas inhibition of oxidative metabolism or RNAi-mediated knockdown of PGC-1beta attenuates this immune response. These data elucidate a molecular pathway that directly links mitochondrial oxidative metabolism to the anti-inflammatory program of macrophage activation, suggesting a potential role for metabolic therapies in treating atherogenic inflammation.
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            AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.

            Replicative cell division is an energetically demanding process that can be executed only if cells have sufficient metabolic resources to support a doubling of cell mass. Here we show that proliferating mammalian cells have a cell-cycle checkpoint that responds to glucose availability. The glucose-dependent checkpoint occurs at the G(1)/S boundary and is regulated by AMP-activated protein kinase (AMPK). This cell-cycle arrest occurs despite continued amino acid availability and active mTOR. AMPK activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate AMPK-dependent cell-cycle arrest. AMPK-induced p53 activation promotes cellular survival in response to glucose deprivation, and cells that have undergone a p53-dependent metabolic arrest can rapidly reenter the cell cycle upon glucose restoration. However, persistent activation of AMPK leads to accelerated p53-dependent cellular senescence. Thus, AMPK is a cell-intrinsic regulator of the cell cycle that coordinates cellular proliferation with carbon source availability.
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              p53 regulates mitochondrial respiration.

              The energy that sustains cancer cells is derived preferentially from glycolysis. This metabolic change, the Warburg effect, was one of the first alterations in cancer cells recognized as conferring a survival advantage. Here, we show that p53, one of the most frequently mutated genes in cancers, modulates the balance between the utilization of respiratory and glycolytic pathways. We identify Synthesis of Cytochrome c Oxidase 2 (SCO2) as the downstream mediator of this effect in mice and human cancer cell lines. SCO2 is critical for regulating the cytochrome c oxidase (COX) complex, the major site of oxygen utilization in the eukaryotic cell. Disruption of the SCO2 gene in human cancer cells with wild-type p53 recapitulated the metabolic switch toward glycolysis that is exhibited by p53-deficient cells. That SCO2 couples p53 to mitochondrial respiration provides a possible explanation for the Warburg effect and offers new clues as to how p53 might affect aging and metabolism.
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                Author and article information

                Journal
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                Molecular Diversity Preservation International (MDPI)
                1422-0067
                May 2009
                19 May 2009
                : 10
                : 5
                : 2252-2303
                Affiliations
                [1 ] Department of Pathophysiology, University of Tartu, Tartu, Estonia; E-Mail: marju.gruno@ 123456ut.ee (M.G.)
                [2 ] Department of Surgery, University of Tartu, Tartu, Estonia; E-Mail: ants.peetsalu@ 123456ut.ee (A.P.)
                [3 ] KeyNeurotek AG, ZENIT-Technology Park Magdeburg, Magdeburg, Germany; E-Mails: zemfira.gizatullina@ 123456rambler.ru (Z.G.); Doreen.Jerzembek@ 123456gmx.de (D.J.); Msmaria1987@ 123456aol.com (M.S.); jegorov@ 123456gmx.de (K.J.); frank.striggow@ 123456keyneurotek.de (F.S.); frank.gellerich@ 123456keyneurotek.de (F.N.G.)
                [4 ] Department of Medical Genetics, University of Tübingen, Tübingen, Germany; E-Mail: hoa.nguyen@ 123456med.uni-tuebingen.de (H.P.N.)
                [5 ] Department of Neurology, Otto von Guericke University, Magdeburg, Germany; E-Mail: stefan.vielhaber@ 123456med.ovgu.de (S.V.)
                [6 ] Bernstein Institute for Physiology, Martin-Luther-University Halle-Wittenberg, Germany; E-Mail: manfred.wussling@ 123456medizin.uni-halle.de (M.H.P.W.)
                [7 ] Institute for Biomedical Research, Kaunas University of Medicine, Kaunas, Lithuania; E-Mails: sonatai@ 123456centras.lt (S.T.); arandarcikaite@ 123456yahoo.com (O.A.)
                [8 ] Department of Neurology, Martin-Luther-University Halle-Wittenberg, Germany; E-Mail: stephan.zierz@ 123456medizin.uni-halle.de (S.Z.)
                Author notes
                [* ] Author to whom correspondence should be addressed; E-Mail: enn.seppet@ 123456ut.ee ; Tel. +372 7374371; Fax: +372 7374372
                Article
                ijms-10-02252
                10.3390/ijms10052252
                2695278
                19564950
                a6d82273-3a34-4b2b-9c32-c86d01538954
                © 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 7 April 2009
                : 25 April 2009
                : 14 May 2009
                Categories
                Review

                Molecular biology
                mitochondria,inflammation,hypoxia,mitochondrial cell death,cancer,energy depression,neurodegenerative diseases

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