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      Uncoupling of oxidative phosphorylation and ATP synthase reversal within the hyperthermic heart

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          Abstract

          Heart failure is a common cause of death with hyperthermia, and the exact cause of hyperthermic heart failure appears elusive. We hypothesize that the energy supply (ATP) of the heart may become impaired due to increased inner‐mitochondrial membrane permeability and inefficient oxidative phosphorylation (OXPHOS). Therefore, we assessed isolated working heart and mitochondrial function. Ex vivo working rat hearts were perfused between 37 and 43.5°C and showed break points in all functional parameters at ~40.5°C. Mitochondrial high‐resolution respirometry coupled to fluorometry was employed to determine the effects of hyperthermia on OXPHOS and mitochondrial membrane potential (Δ Ψ) in vitro using a comprehensive metabolic substrate complement with isolated mitochondria. Relative to 37 and 40°C, 43°C elevated Leak O 2 flux and depressed OXPHOS O 2 flux and ∆ Ψ. Measurement of steady‐state ATP production from mitochondria revealed decreased ATP synthesis capacity, and a negative steady‐state P:O ratio at 43°C. This approach offers a more powerful analysis of the effects of temperature on OXPHOS that cannot be measured using simple measures such as the traditional respiratory control ratio (RCR) or P:O ratio, which, respectively, can only approach 1 or 0 with inner‐membrane failure. At 40°C there was only a slight enhancement of the Leak O 2 flux and this did not significantly affect ATP production rate. Therefore, during mild hyperthermia (40°C) there is no enhancement of ATP supply by mitochondria, to accompany increasing cardiac energy demands, while between this and critical hyperthermia (43°C), mitochondria become net consumers of ATP. This consumption may contribute to cardiac failure or permanent damage during severe hyperthermia.

          Abstract

          e12138

          Intact cardiac function is crucial, and is particularly important for mediating thermoregulation in hyperthermic states. However, the heart's aerobic metabolism is also thermally sensitive, and may become limited at extreme physiological temperatures. We have shown that at 43°C there is a loss of mitochondrial membrane potential, and this subsequently drives a reversal of the mitochondrial the F 1F 0‐ATP synthase where it becomes a net consumer of ATP.

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          Determination of serum proteins by means of the biuret reaction.

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            Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes.

            The network for cardiac fuel metabolism contains intricate sets of interacting pathways that result in both ATP-producing and non-ATP-producing end points for each class of energy substrates. The most salient feature of the network is the metabolic flexibility demonstrated in response to various stimuli, including developmental changes and nutritional status. The heart is also capable of remodeling the metabolic pathways in chronic pathophysiological conditions, which results in modulations of myocardial energetics and contractile function. In a quest to understand the complexity of the cardiac metabolic network, pharmacological and genetic tools have been engaged to manipulate cardiac metabolism in a variety of research models. In concert, a host of therapeutic interventions have been tested clinically to target substrate preference, insulin sensitivity, and mitochondrial function. In addition, the contribution of cellular metabolism to growth, survival, and other signaling pathways through the production of metabolic intermediates has been increasingly noted. In this review, we provide an overview of the cardiac metabolic network and highlight alterations observed in cardiac pathologies as well as strategies used as metabolic therapies in heart failure. Lastly, the ability of metabolic derivatives to intersect growth and survival are also discussed.
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              Mitochondria in health and disease: perspectives on a new mitochondrial biology.

              The integrity of mitochondrial function is fundamental to cell life. It follows that disturbances of mitochondrial function will lead to disruption of cell function, expressed as disease or even death. In this review, I consider recent developments in our knowledge of basic aspects of mitochondrial biology as an essential step in developing our understanding of the contributions of mitochondria to disease. The identification of novel mechanisms that govern mitochondrial biogenesis and replication, and the delicately poised signalling pathways that coordinate the mitochondrial and nuclear genomes are discussed. As fluorescence imaging has made the study of mitochondrial function within cells accessible, the application of that technology to the exploration of mitochondrial bioenergetics is reviewed. Mitochondrial calcium uptake plays a major role in influencing cell signalling and in the regulation of mitochondrial function, while excessive mitochondrial calcium accumulation has been extensively implicated in disease. Mitochondria are major producers of free radical species, possibly also of nitric oxide, and are also major targets of oxidative damage. Mechanisms of mitochondrial radical generation, targets of oxidative injury and the potential role of uncoupling proteins as regulators of radical generation are discussed. The role of mitochondria in apoptotic and necrotic cell death is seminal and is briefly reviewed. This background leads to a discussion of ways in which these processes combine to cause illness in the neurodegenerative diseases and in cardiac reperfusion injury. The demands of mitochondria and their complex integration into cell biology extends far beyond the provision of ATP, prompting a radical change in our perception of mitochondria and placing these organelles centre stage in many aspects of cell biology and medicine.
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                Author and article information

                Journal
                Physiol Rep
                Physiol Rep
                physreports
                phy2
                Physiological Reports
                Wiley Periodicals, Inc.
                2051-817X
                September 2014
                28 September 2014
                : 2
                : 9
                : e12138
                Affiliations
                [1 ]School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand
                [2 ]Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
                [3 ]Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
                [4 ]Maurice Wilkins Center, University of Auckland, Auckland, New Zealand
                Author notes
                CorrespondenceAmelia Power, Applied Surgery and Metabolism, School of Biological Sciences, Thomas Building, 3a Symonds Street, Auckland 1142, New Zealand. Tel: 6493737599 extn 81854 Fax: 6493737045 E‐mail: a.power@ 123456auckland.ac.nz
                Article
                phy212138
                10.14814/phy2.12138
                4270237
                25263202
                4d157c40-293c-4118-a00f-3766546f176c
                © 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 07 August 2014
                : 08 August 2014
                Categories
                Original Research

                atp synthesis,hyperthermia,mitochondrial membrane potential,mitochondrial respiration

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