ADVANCES IN BIOCHEMISTRY IN HEALTH AND DISEASE

Transcription

1 Mitochondria

2 ADVANCES IN BIOCHEMISTRY IN HEALTH AND DISEASE Series Editor: Naranjan S. Dhalla, PhD, MD (Hon), DSc (Hon) Winnipeg, Manitoba Canada Editorial Board: A. Angel, Toronto, Canada; I. M. C. Dixon, Winnipeg, Canada; L. A. Kirshenbaum, Winnipeg, Canada; Dennis B. McNamara, New Orleans, Louisiana; M. A. Q. Siddiqui, Brooklyn, New York; A. K. Srivastava, Montreal, Canada Volume 1: S. K. Cheema (ed.), Biochemistry of Atherosclerosis Volume 2: S. W. Schaffer and M-Saadeh Suleiman (eds.), Mitochondria: The Dynamic Organelle

3 Mitochondria The Dynamic Organelle Edited by Stephen W. Schaffer University of South Alabama, Mobile, AL and M-Saadeh Suleiman Bristol Royal Infirmary, Bristol, United Kingdom

4 Stephen W. Schaffer Department of Pharmacology University of South Alabama Mobile, AL USA M-Saadeh Suleiman Bristol Royal Infirmary Bristol BS2 8HW UNITED KINGDOM ISBN-13: e-isbn-13: Library of Congress Control Number: Springer Science +Business Media, LLC All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. Printed on acid-free paper springer.com

5 Preface The term mitochondrion is derived from Latin, with mitos meaning thread and chondrion meaning granules. Indeed, under the light microscope, mitochondria often appear as rods or granules within the cytoplasm. For decades after initial visualization of mitochondria by light microscopy, mitochondrial function remained clouded. However, with the development of differential centrifugation and electron microscopy, it was discovered that a chief function of the mitochondria was the generation of ATP for the remainder of the cell. For many years, the energy generating function of the mitochondria was considered the primary, if not the sole function of the mitochondria. During that period, investigators attempted to obtain information on the mechanism of ATP synthesis and the regulation of electron transport. In the first chapter of the book, Dr. Hassinen summarizes those studies, providing clear pictures on the transformation of reducing equivalents into a proton gradient and the mechanism by which the F 1 F 0 ATPase utilizes the proton gradient to generate ATP. He also summarizes the key regulatory steps of the citric acid cycle, which is the major source of reducing equivalents for the electron transport chain. In the heart, most of the carbon that feeds into the citric acid cycle is derived from fatty acid metabolism. Although fatty acid utilization provides most of the ATP for contraction, a proper balance must be maintained between the utilization of fatty acids and that of glucose. In the second chapter, Drs. Folmes and Lopaschuk discuss the interrelationship between carbohydrate and fatty acid metabolism and how the interrelationship is affected in various disease states. Correction of metabolic dysregulation is introduced as a novel approach toward the treatment of heart disease. In the third chapter, Drs. Sugden and Holmes describe the profound influence of the nuclear regulators, known as the peroxisome proliferator-activated receptors (PPARs), on lipid and carbohydrate metabolism. The physiological and pharmacological ligands that activate the receptors are discussed, along with pathological conditions associated with dysregulation of the receptors. Today, it appears that crosstalk between the mitochondria and the remainder of the cell is an extremely important function of the mitochondria. Not only do the mitochondria provide metabolites to ensure continuation of several metabolic pathways, but they also regulate the levels of key cytosolic constituents. This is made possible by the presence of transporters in the inner mitochondrial membrane that specifically regulate the movement of substrates in and out of the mitochondria. In the fourth chapter, Drs. Kaplan and Mayor describe the structure of a transport protein that shuttles citrate out of the mitochondria, v

6 vi Preface providing a carbon source for fatty acid, triglyceride and cholesterol biosynthesis. The chapter also clarifies the mechanism by which the transporter insures the integrity of the membrane barriers protecting the mitochondria from the accumulation of undesirable substances. In chapter 5, Dr. Vary outlines the role of mitochondria in ammonia detoxification, gluconeogenesis, protein synthesis and acid-base balance. The complex regulation of rate-limiting mitochondrial events, such as flux through pyruvate and branched chain ketoacid dehydrogenases, by transcription factors, hormones and cellular nutrition are reviewed. In chapter 6, Dr. King discusses the important role played by the mitochondria in amino acid metabolism. She reviews evidence that amino acids are involved in mitochondrial-dependent cytoprotective reactions that are dependent on amino acid metabolism rather than protein synthesis. Mitochondria are dynamic organelles. They can migrate, undergo morphological changes and accumulate in response to physiological and pathological biogenetic stimuli. Dr. Al-Mehdi summarizes the dynamic changes induced upon endothelial mitochondria by shear-stress, flow adaptation and flow cessation. Recent studies suggest that the mitochondria may also generate initiators of important signaling pathways. Of particular interest is the activation of cell altering protein kinases by mitochondrial-generated free radicals. How the mitochondria maintain a balance between the generation and destruction of reactive oxygen and nitrogen species is presently unclear. Dr. Turrens argues that it is a complex process, involving multiple sources of reactive oxygen species, several antioxidant enzymes, antioxidant vitamins and an assortment of antioxidant small molecules, all which normally act to prevent the accumulation of damaging levels of oxidants. Like reactive oxygen species, mitochondrial calcium homeostasis must be tightly regulated to ensure mitochondrial and cellular viability. In chapter 9, Drs. Griffiths, Bell, Balaska and Rutter discuss the transporters involved in calcium accumulation by the mitochondria. They also discuss the coupling mechanisms that link modest mitochondrial calcium accumulation with the stimulation of energy production. Also addressed in the chapter are potential pharmacological interventions that might be expected to prevent the damaging effects of excessive mitochondrial calcium accumulation that arise in certain pathological states. Besides the transport of calcium, the mitochondria also regulate the transport of other cations. In chapter 10, Dr. O Rourke assigns an important cytoprotective role to the potassium channels. He describes experimental evidence showing that multiple potassium channels are cytoprotective, however, he argues that the lack of structure/function relationships has limited the development of ion selective agents with therapeutic significance. Failure to maintain proper levels of calcium and reactive species within the mitochondria alters mitochondrial function, leading to the formation of the mitochondrial permeability transition pore. The formation of the pore renders the mitochondria leaky to organic and inorganic solutes, causing it to lose the ability to generate ATP and to control matrix volume. Drs. Halestrap, Clarke and Khalilin describe the properties of the pore, including the importance of the mitochondrial permeability transition in the depletion of cellular ATP and the loss of cell viability. They point out that events that accompany ischemiareperfusion, such as reactive oxygen species generation, calcium overload,

7 Preface vii adenine nucleotide depletion, inorganic phosphate accumulation and collapse of the membrane potential, act as initiators or facilitators of pore formation. It follows that effective therapy against ischemia-reperfusion damage requires rapid closing of the mitochondrial permeability transition pore. In chapter 12, Drs. Suleiman and Schaffer review the mechanisms underlying the onset of cellular apoptosis, an orderly type of death that is initiated either by intrinsic, mitochondrial events or by extrinsic stimuli. Because apoptosis is genetically programmed and proceeds along specified pathways, it is highly regulated. Drs. Suleiman and Schaffer describe the effects of several cardioactive agents, including angiotensin II, calcium, reactive species and -adrenergic agonists, on the apoptotic pathway. They maintain that the inhibition of apoptosis might serve as an important therapeutic approach in the treatment of heart disease. Traditionally, apoptosis and necrotic oncosis represent distinct pathways, with only apoptosis considered a highly regulated, genetically programmed pathway. However, in chapter 13, Drs. Murphy and Steenbergen argue that the two forms of cell death share common steps in accidental insults, such as ischemia-reperfusion. They point out that in both forms of cell death, the mitochondria serve as a source of reactive oxygen species and other pro-apoptotic factors, can contribute to ATP depletion and modulate calcium homeostasis. Therefore, they maintain that a better understanding of mitochondrial regulation should provide novel therapeutic approaches for reducing both apoptosis and necrosis. One mechanism of protecting the cell against both forms of death is preconditioning. In chapter 14, Drs. Phillip, Downey and Cohen propose a signaling cascade triggered by G i coupled receptors that lead to the opening of the K ATP channel. They suggest that attenuation of the mitochondrial permeability transition may serve as the end effector of the preconditioning event. In chapter 15, Drs. Shokolenko, LeDoux and Wilson ascribe a key role for mitochondrial DNA damage in apoptosis. They point out that mitochondrial DNA is much more susceptible to oxidative damage than nuclear DNA. Moreover, the synthesis of most mitochondrially expressed peptides is regulated by a single promoter. Since the proteins encoded by the mitochondria are components of electron transport, mitochondrial DNA damage reduces flux through the electron transport and enhances generation of superoxide. Therefore, it is logical to propose that mitochondrial DNA repair, by reversing mitochondrial DNA damage, can rescue cells from excessive superoxide generation and oxidant-induced apoptosis. Recent evidence that mitochondria are directly involved in cell signaling initiated by pro-apoptotic factors, as well as cell survival stimuli, indicates that the status of the mitochondria determines the viability of the cell. Future therapy is likely to take advantage of this central role of the mitochondria to shift the balance in favor of either cell survival or death. Moreover, with the emergence of mitochondria as an important regulator of cell signaling, new interest in the pathophysiology of the mitochondria should yield fascinating results. Stephen W. Schaffer M-Saadeh Suleiman

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9 Contents Part 1 Mitochondrial Metabolism 1. Regulation of Mitochondrial Respiration in Heart Muscle... 3 Ilmo Hassinen 2. Regulation of Fatty Acid Oxidation of the Heart Clifford D. L. Folmes and Gary D. Lopaschuk 3. Regulation of Mitochondrial Fuel Handling by the Peroxisome Proliferator-Activated Receptors Mary C. Sugden and Mark J. Holness 4. Molecular Structure of the Mitochondrial Citrate Transport Protein Ronald S. Kaplan and June A. Mayor 5. Regulation of Pyruvate and Amino Acid Metabolism Thomas C. Vary, Wiley W. Souba and Cristopher J. Lynch 6. Amino Acids and the Mitochondria Nicola King Part 2 The Dynamic Nature of the Mitochondria 7. Mechanotransduction of Shear-Stress at the Mitochondria Abu-Bakr Al-Mehdi Part 3 Mitochondria as Initiators of Cell Signaling 8. Formation of Reactive Oxygen Species in Mitochondria Julio F. Turrens 9. Mitochondrial Calcium: Role in the Normal and Ischaemic/ Reperfused Myocardium Elinor J. Griffiths, Christopher J. Bell, Dirki Balaska and Guy A. Rutter ix

10 x Contents 10. Mitochondrial Ion Channels Brian O Rourke Part 4 Mitochondria as Initiators of Cell Death 11. The Mitochondrial Permeability Transition Pore from Molecular Mechanism to Reperfusion Injury and Cardioprotection Andrew P. Halestrap, Samantha J. Clarke and Igor Khalilin 12. The Apoptotic Mitochondrial Pathway Modulators, Interventions and Clinical Implications M-Saadeh Suleiman and Stephen W. Schaffer 13. The Role of Mitochondria in Necrosis Following Myocardial Ischemia-Reperfusion Elizabeth Murphy and Charles Steenbergen Part 5 Mitochondria as Modulators of Cell Death 14. Mitochondria and Their Role in Ischemia/Reperfusion Injury Sebastian Phillip, James M. Downey and Michael V. Cohen 15. Mitochondrial DNA Damage and Repair Inna N. Shokolenko, Susan P. Ledoux and Glenn L. Wilson Index