416 Cold Defence Responses: the Role of Oxidative Stress Dusko P. Blagoje

[Frontiers in Bioscience S3, 416-427, January 1, 2011] Cold defence responses: the role of oxidative stress Dusko P. Blagojevic1, Gordana N. Grubor-Lajsic2 and Mihajlo B. Spasic1 1Department of Physiology, Institute for Biological Research Sinisa Stankovic, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia,2Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovica 2, 21000 Novi Sad, Serbia TABLE OF CONTENTS 1. Abstract 2. Introduction 2.1. Reactive oxygen species 2.2. Anti-oxidative defence and cellular redox state 2.3. Oxidative stress 2.4. Redox cellular signalling 3. Models for studying cold anti-oxidative defence responses 3.1. Endotherms 3.2. Heterotherms 4. Cold anti-oxidative defence responses 4.1. Acute cold exposure 4.2. Chronic cold exposure 4.3. Tissue specificity 5. Cellular redox signalling and regulation of anti-oxidative processes during cold exposure 6. Acknowledgements 7. References 1. ABSTRACT 2. INTRODUCTION Low temperatures provoke increased production Stable conditions favour survival of a biological of heat accompanied by increased respiration, oxygen system within its environment. According to non- consumption and the production of partially reduced equilibrium thermodynamics internal homeostasis describes oxygen species called ROS. ROS induce different forms of a stationary state of non-equilibrium. For spontaneously cellular oxidative damage, disturb the redox state and can stable states to occur a lowered metabolic rate, withdrawal change the activity of several metabolic enzymes. of sympathetic drive and reinforcement of vagal heart tone Organisms have developed a functionally connected set of and circulation are required. This confirms that the anti-oxidant enzymes and low molecular mass compounds parasympathetic division of the autonomic nervous system (together termed the ADS) that metabolise primary ROS. If is the main controller of homeostasis (1). Heat production ROS production within cells overwhelms the ADS, occurs in living organisms and the “metabolic rate” is oxidative damage arises and oxidative stress can occur. commonly defined as “the rate of heat production” (2). The Short-term cold exposure in endotherms leads to oxidative latter depends on the level of adenosine triphosphate (ATP) stress. As cold exposure persists organisms develop that is mainly produced by mitochondrial oxidative adaptive changes toward reducing ROS production and phosphorylation. Inevitably the production of partially increasing the ADS. In contrast, heterotherms and reduced oxygen and the formation of ROS occurs. ectotherms as a normal part of their over-wintering strategy However, respiration is not just about generating energy, slow down metabolism, oxygen consumption and it’s also about generating feedback that stimulates a cell to subsequently cause ROS production. Increased baseline recognise and respond to its environment and blocking activity of key anti-oxidant enzymes as well as 'secondary' respiration generates chemical signals in the form of ROS enzymatic defence and/or glutathione levels in preparation (3). Precise relationships between heat production, ROS, for a putative oxidative stressful situation arising from the ADS and physiological states are still poorly defined. tissue re-oxygenation seems to be the preferred Low temperatures provoke physiological responses related evolutionary adaptation of such animals exposed to low to heat production, induce phase changes in energy environmental temperatures. production, oxygen consumption and subsequent ROS 416 Cold defence and oxidative stress •− production. Exposure to low temperature alters the ADS that this mode of O2 production might account for most of •− activity, its composition and its structure with respect to its the overall exposure of mitochondria to O2 . The •− individual components which strive to provide the best maximum O2 production rate in vivo is proportional to the possible protection and preservation of cellular content of respiratory complexes such as complex I and homeostasis. By understanding the mechanisms of thus correlates with the maximum respiration rate. Little is •− physiological regulation, underlining cold defence can known about the actual flux of O2 within mitochondria in provide information regarding the regulation of cellular vivo, about how it changes under different physiological homeostasis, particularly with respect to hibernation and circumstances, or about its quantitative importance relative + insect dormancy. A reduction in the relative mass of heat- to other sources of ROS. NADH/NAD , CoQH2/CoQ ratios producing organs in heat-adapted animals has been found and the local O2 concentration are all highly variable and to be associated with a reduction in the metabolic rate and a difficult to measure in vivo. Therefore, the estimation of •− •− similar reduction in the oxidative enzyme activity in liver O2 generation in isolated mitochondria in vivo from O2 mitochondria and liver glucose 6-phosphatase activity. production rates is not possible (6). Adaptation to 30oC, from the point of view of •− mitochondrial protein synthesis, is characterised by the O2 itself is relatively un-reactive but is a disbalance between its rate of synthesis and degradation great promoter of further cellular oxidative reactions. •− and its decreased ATPase activity as a consequence of The cytotoxicity of O2 in vivo comes from its • depressed thyroid activity in warm conditions. In general, protonated form HO2 formed via the Haber-Weiss and chemical thermo-suppression seems to occur in cells of Fenton reactions, the production of peroxynitrite − • •− various organs and tissues during heat acclimation (4). On (ONOO ) from nitric oxide (NO ) and the ability of O2 the other hand, metabolic suppression in cold-adapted to oxidise [4Fe-S]2+ clusters of several enzymes leading animals, hibernators or insects, in the form of dormancy is to release of iron which can further promote Fenton poorly understood. Furthermore, cold survival mechanisms chemistry (10). The other two ROS originating from the • are complex involving anti-oxidant molecules. Future above-mentioned reactions are H2O2 and OH . The studies examining cold exposure, cold adaptation and former is also generally poorly reactive. It crosses cell animal hibernation will establish detailed relationships membranes by diffusion or facilitated by aquaporins and between heat production, ROS production, ADS activity initiates further cellular oxyradical reactions. In the 2+ + and these related processes. presence of iron (Fe ) or copper (Cu ) H2O2 can be split into OH• and hydroxyl anions (OH-), the latter 2.1. Reactive oxygen species (ROS) being the main cellular precursor of OH• (11). Once During metabolism production of superoxide generated OH• reacts with molecules in their immediate •− anion radicals (O2 ), hydrogen peroxide (H2O2), hydroxyl vicinity generating and promoting site-specific oxidative radicals (OH.), lipid radicals (L.) and peroxides (LOOH) damaged molecules (12). If OH• collides with a occurs. Cellular ROS generators are diverse; the principal membrane lipid (LH) molecule a self-propagated lipid generator is the mitochondrial respiratory process, which peroxidation chain reaction generates lipid peroxides •− yields O2 (5,6). However, mitochondrial ROS production resulting in the disturbance of membrane function. If not is not a simple bi-product of mitochondrial respiration and eliminated ROS can induce oxidative damage within every oxygen consumption as total rates of ROS generation in class of all cellular molecules. different tissues are not linked to their differences in oxygen consumption (7). In vivo the one-electron reduction ROS are capable of inhibiting or changing the •− of O2 to O2 is thermodynamically favoured and activity of several metabolic enzymes. H2O2 inhibits •− mitochondrial O2 production takes place at redox-active glyceraldehyde 3-phosphate dehydrogenase by oxidation of prosthetic groups within proteins or when electron carriers its -SH groups (13). ROS also affect ADS enzymes that are such as reduced coenzyme Q (CoQH2) are bound to responsible for modulating the extent and types of ROS in •− •− proteins (8). The flux of O2 within the matrix of cells. A high level of O2 can inactivate catalase (CAT) mammalian mitochondria is related to the concentration of (14). Cu,Zn-containing superoxide dismutase (CuZnSOD potential electron donors including the NADH/NAD+ and or SOD1) activity decreases due to inactivation by OH• and • CoQH2/CoQ ratios, the local concentration of O2 and the H2O2 (15,16). NO reversibly binds to the haem groups second-order rate constants for the reactions between them. within CAT and decreasing its activity. In addition, ONOO- •− Significant O2 production arises from complex I when the can inhibit CAT. Manganese-containing superoxide mitochondria do not produce ATP, have a high proton dismutase (MnSOD or SOD2) stimulates NO• decay motive force and a reduced CoQ pool and when there is a leading to partial enzyme inactivation, changing the levels + . - high NADH/NAD ratio in the mitochondrial matrix (9). of NO , ONOO and H2O2 (17). Furthermore, recent results •− Therefore, the production of O2 in mitochondria is have showed ROS/RNS cross regulation of iNOS activity • •− continuous, but its extent depends on the cellular redox shifting the balance towards NO and O2 production (18). state and the amount of available O2. Many enzymes and This oxidant-mediated

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