Handbook of Mitochondrial Dysfunction

Shamim I. Ahmad

• Publisher: CRC Press
• Year: 2019
• Print ISBN: 9781138336087
• eBook ISBN: 9780429811760
• Topic: Medicine
• Subtopic: Biochemistry in Medicine

Mitochondria produce the chemical energy necessary for eukaryotic cell functions; hence mitochondria are an essential component of health, playing roles in both disease and aging. More than 80 human diseases and syndromes are associated with mitochondrial dysfunction; this book focuses upon diseases linked to these ubiquitous organelles. Accumulation of mitochondrial DNA damage results in mitochondrial dysfunction through two main pathways. Mutation in mitochondrial DNA causes diseases such as Kearns-Sayre syndrome and Pearson syndrome. Mutation in chromosomal DNA causes diseases such as Parkinson's disease and schizophrenia. These and many other diseases are reviewed in this book.

Key Features

• Presents the detailed structure of mitochondria, mitochondrial function, roles of oxidants and antioxidants in mitochondrial dysfunction.
• Includes summary of both causes and effects of these diseases.
• Discusses current and potential future therapies for mitochondrial dysfunction diseases
• Explores a wide variety of diseases caused by dysfunctional mitochondria.

1 Mitochondrial Structure and Function

Marcos Roberto de Oliveira

Grupo de Estudos em Neuroquímica e Neurobiologia de Moléculas Bioativas, Universidade Federal de Mato Grosso (UFMT), Av. Fernando Corrêa da Costa, Cuiaba, MT, Brazil

CONTENTS

1 Introduction

2 Conclusion

References

1 INTRODUCTION

The mitochondria exhibit a double-membrane structure that is crucial to the role these organelles present in the fungi, plant, and animal cells [1]. The outer and the inner mitochondrial membranes (OMM and IMM, respectively) limit the intermembrane space (IMS), whose function will be discussed here [1] (Figure 1). The IMM presents several cristae, which are folds of the IMM extended into the mitochondrial matrix, a compartment in which metabolic enzymes and signaling agents are found [2]. Moreover, mitochondria contain DNA in the mitochondrial matrix [3]. The mitochondrial DNA is usually a circular molecule (16,569-bp) and multiple copies are present in each organelle [4]. Both mitochondrial and nuclear genomes are necessary in order to maintain the mitochondrial function [5]. Actually, the mitochondrial genome may encode more than 13 proteins, which are associated with mitochondrial function in humans [6]. Furthermore, the human mitochondrial genome encodes 24 structural RNAs, which are necessary in the translation process in the mitochondria [6]. Nonetheless, the mitochondria depend to a great extent on the nuclear genome in order to maintain the complete expression of their proteins (it has been estimated that more than 1,000 mitochondria-located proteins are encoded by the nuclear genome) [3–5].

FIGURE 1 The mitochondrial morphology: The mitochondria contain the outer and the inner mitochondrial membranes (OMM and IMM, respectively) and the intermembrane space (IMS) surrounded by those membranes. The IMM contains the cristae that extend into the mitochondrial matrix. The mitochondrion image was obtained from Pixabay website, which gently distributes free images to be used commercially.

The major function of mitochondria is to produce adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate (Pi) in the oxidative phosphorylation (OXPHOS) system [7] (Figure 2). Besides, mitochondria play a crucial role in the calcium (Ca²⁺) ions homeostasis and in the heme biosynthesis [1,7]. The electron transfer chain (ETC), which is found in the IMM, is part of the OXPHOS system and comprises the complexes I (NADH dehydrogenase), II (succinate dehydrogenase), III (coenzyme Q – cytochrome c reductase), and IV (cytochrome c oxidase) [7]. In addition, there are mobile components responsible for the transfer of electrons between the complexes, namely coenzyme Q (so called ubiquinone) and cytochrome c [8]. Coenzyme Q carries electrons from the complexes I and II, as well as from other proteins, to the complex III, from which cytochrome c transfers one electron at a time to the complex IV [9]. The transfer of electrons between the complexes is associated with the pumping of protons (H⁺) from the mitochondrial matrix to the IMS by the complexes I, III, and IV [7]. These protein complexes function as H⁺ pumps and use the energy released from the flux of electrons in the ETC to generate an electrochemical gradient across the IMM [7,9]. This is the mitochondrial membrane potential (MMP) and it depends on the function of the complexes and on the integrity of the mitochondrial membranes in order to be generated. The accumulation of H⁺ in the IMS is necessary to the complex V synthesizes ATP from ADP and Pi [7,9]. Therefore, loss of MMP represents a decrease ability in the mitochondria to produce ATP and also a signal of mitochondrial dysfunction due to several types of insults [7,9].

FIGURE 2 An overview of the mitochondrial oxidative phosphorylation (OXPHOS) system. The OXPHOS system comprises the electron transfer chain (ETC) and the complex V (ATP synthase/ATPase). The mitochondrion image was obtained from Pixabay website, which gently distributes free images to be used commercially.

The major sources of electrons to the ETC include the reduced forms of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH₂), which contains electrons obtained from several metabolic substrates that are oxidized in certain metabolic pathways, such as the tricarboxylic acid cycle (TCA, the so-called Krebs cycle), the oxidation of fatty acids and ketone bodies, and the oxidation of some α-ketoacids obtained from the degradation of amino acids, depending on the cell type [7]. The glycolysis is also an indirect source of electrons to the ETC by the electron shuttles (namely malate-aspartate shuttle and glycerol-3-phosphate shuttle), since there is not a specific transport to NADH from the cytoplasm to the mitochondrial matrix [10,11]. In the complex IV, these electrons bind to oxygen (O₂), the final electron acceptor, and water is produced [7]. Therefore, O₂ is necessary to mammalian cells in order to amplify the production of ATP in the mitochondria. Without O₂, it is impossible to mitochondria continue oxidizing the metabolic substrates and the production of ATP declines. In this context, electron leakage from the ETC leads to the production of ROS, mainly the superoxide anion radical (O₂^−•) [12,13].

Actually, the mitochondria are the main source of ROS in the mammalian cells [13]. The manganese-dependent superoxide dismutase (Mn-SOD) enzyme (which is located in the mitochondria) converts O₂^−• into hydrogen peroxide (H₂O₂), a non-radical species [13]. H₂O₂ then reacts with glutathione peroxidase (GPx), giving rise to water [14]. Other enzymes can metabolize H₂O₂, decreasing the chance this molecule would react with iron and cupper ions (in the Fenton chemistry reaction) or with O₂^−• (in the Haber-Weiss reaction) [13–15]. Mitochondrial impairment in the brain is cause of concern due to the increase in the production of ROS it promotes in a very unstable environment [16]. Brain consumes O₂ at very high rates and presents high concentrations of transition metals (mainly iron and cupper), as well as contains lipids in elevated concentrations [17]. Despite this, the brain contains low concentrations of antioxidants [17]. Therefore, the brain is very sensitive to redox disturbances originated or not from the mitochondria. The strategies aiming to promote mitochondrial protection involves upregulation of antioxidant enzymes located in the organelles and induction of the synthesis of reduced glutathione (GSH), the major non-enzymatic antioxidant in mammalian cells, which is found at high concentrations inside the mitochondria [18,19]. Recently, several works published by our research group have demonstrated a crucial role for the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in modulating mitochondrial protection [20–27]. Nrf2 is the master regulator of the redox environment in mammalian cells and presents a role in the maintenance of mitochondrial function and dynamics [28–30]. Nrf2 modulates the expression of the antioxidant enzymes glutathione peroxidase (GPx), glutathione reductase (GR), γ-glutamylcysteine ligase (γ-GCL), and heme oxygenase-1 (HO-1), to cite a few [29]. Moreover, Nrf2 regulates the expression of phases II (conjugation) and III (excretion) detoxification enzymes, including glutathione-S-transferase (GST) and multidrug resistance-associated proteins (MRP), among others [31].

Mitochondrial biogenesis, so called mitogenesis, is the biological event in which new mitochondria are generated in mammalian cells [32]. Mitochondrial biogenesis involves the activation of a signaling pathway modulated by the adenosine monophosphate-activated kinase (AMPK), sirtuin 1 (SIRT1, NAD⁺-dependent deacetylase), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), as previously reviewed [33]. The activation of PGC-1α causes the upregulation of the transcription factors nuclear respiratory factor-1 (NRF-1) and nuclear respiratory factor-2 (NRF-2) and of the estrogen-related receptor α (ERRα) [34–36]. These proteins mediate the transcription of nuclear genes encoding mitochondria-related proteins [37]. For example, the expression of the mitochondrial transcription factor A (TFAM), B1 (TFB1M), and B2 (TFB2M) is enhanced and causes modifications necessary in the mitochondrial DNA in order to the synthesis of mitochondrial RNA begins. The activation of AMPK (that occurs by an increase in the levels of AMP) leads...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Dedication
• Table of Contents
• Preface
• Acknowledgment
• About the Editor
• Contributors
• SECTION I: Introduction Structure and Function of Mitochondria
• 1. Mitochondrial Structure and Function
• 2. Structure, Function and Evolutionary Aspects of Mitochondria
• 3. Mitochondrial Genome Damage, Dysfunction and Repair
• SECTION II: Mitochondrial Dysfunction and Diseases
• 4. Instability of Human Mitochondrial DNA, Nuclear Genes and Diseases
• 5. Kearns-Sayre Syndrome
• 6. Mitochondrial Dysfunction and Barth Syndrome
• 7. Mitochondrial Dysfunction in the Pathophysiology of Alzheimer’s Disease
• 8. Mitochondrial Dysfunction in Multiple Sclerosis
• 9. Mitochondrial Dysfunction in Chronic Kidney Disease
• 10. Mitochondrial Dysfunction in Breast Cancer A Potential Target from the Bench to Clinical Therapeutics
• 11. Mitochondrial Dysfunction and DNA Methylation in Atherosclerosis
• 12. Mitochondrial Dysfunction and Heart Diseases
• 13. The Role of Mitochondrial Dysfunction in Mitophagy and Apoptosis and Its Relevance to Cancer
• 14. Mitochondrial Dysfunction Linking Obesity and Asthma
• 15. Mitochondrial Dysfunction and Hearing Loss
• 16. Superoxide Dismutase, Mitochondrial Dysfunction, and Neurodegenerative Diseases
• 17. Role of Post-Translational Modifications of Mitochondrial Complex I in Mitochondrial Dysfunction and Human Brain Pathologies
• 18. Heme Oxygenase-1 in Kidney Health and Disease Perspective of Mitochondrial Homeostasis
• 19. Mitochondrial Transplantation in Myocardial Ischemia and Reperfusion Injury
• 20. Mitochondrial Dysfunction in Diabetes
• 21. Clinical Manifestation of Mitochondrial Disorders in Childhood
• 22. Mitochondrial Dysfunction and Epilepsies
• 23. Mitochondrial Dysfunction and Allergic Disease
• SECTION III: Factors Affecting Mitochondrial Function
• 24. Role of Carnosic Acid in Protection of Brain Mitochondria
• 25. Mitochondrial Dysfunction and Its Impact on Oxidative Capacity of Muscle
• 26. The Effects of Resveratrol on the Brain Mitochondria
• 27. Pathophysiology and Biomarkers of Mitochondrial Dysfunction Induced by Heavy Exercise
• 28. Mitochondrial Pathologies and Their Neuromuscular Manifestations
• 29. Mitochondrial Stress and Cellular Senescence
• 30. Role of Mitochondrial Dysfunction in Human Obesity
• 31. Roles of Melatonin in Maintaining Mitochondrial Welfare Focus on Renal Cells
• 32. Mitochondrial Dysfunction Affecting the Peripheral Nervous System in Diabetic Neuropathy and Avenues for Therapy
• 33. Mitochondrial Dysfunction and Oxidative Stress in the Pathogenesis of Metabolic Syndrome
• SECTION IV: Immunity and Toxicity
• 34. Regulation of Antiviral Immunity by Mitochondrial Dynamics
• 35. Mitochondrial Dysfunction, Immune Systems, Their Diseases, and Possible Treatments
• 36. Organophosphorus Compound-Induced Mitochondrial Disruption
• 37. Mitochondrial Dysfunction in Friedreich Ataxia
• Index