Osiewacz The Mitochondrion in Aging and Disease

1. Auflage 2014
ISBN: 978-0-12-394840-3
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 127, 290 Seiten

Reihe: Progress in Molecular Biology and Translational Science

Mitochondria, the 'power plants' of eukaryotic cells, are best known for the generation of adenosine triphosphate (ATP), the universal cellular 'energy currency' of the cell, and the synthesis of different essential components. Mitochondrial dysfunction is known to lead to various degenerative disorders, disease, and aging. The Mitochondrion in Aging and Disease works to unravel the processes leading to mitochondrial impairments and of pathways involved in mitochondrial quality control and their impact on health and aging will be addressed. - Reviews current topics of interest - Written by experts in the field

Autoren/Hrsg.

Osiewacz, H.D.

Inhaltsverzeichnis

1;Front Cover;1
2;The Mitochondrion in Aging and Disease;4
3;Copyright;5
4;Contents;6
5;Contributors;10
6;Preface;12
7;Chapter One: The Mitochondrial Free Radical Theory of Aging;16
7.1;1. Introduction;17
7.2;2. Antioxidants and Longevity;18
7.3;3. Mitochondrial ROS Production and Oxidative Damage in mtDNA;19
7.4;4. Longevity and Membrane Fatty Acid Unsaturation;24
7.5;5. DR, mtROS Production, and Oxidative Damage in mtDNA;26
7.6;6. Protein and Methionine Restriction;27
7.6.1;6.1. Effect on longevity;27
7.6.2;6.2. Role of mtROS generation and oxidative damage;30
7.7;7. Conclusions;35
7.8;Acknowledgments;37
7.9;References;37
8;Chapter Two: Mitochondrial DNA Mutations in Aging;44
8.1;1. Introduction: The Different Faces of the Mitochondrial Theory of Aging;45
8.2;2. Mitochondria, mtDNA, and mtDNA Mutations;47
8.2.1;2.1. Mitochondrial biology and mtDNA;47
8.2.2;2.2. mtDNA mutations;48
8.3;3. Physiological Outcomes of mtDNA Mutations;50
8.3.1;3.1. RC deficiency;50
8.3.2;3.2. Mitochondrial DNA disease;51
8.3.3;3.3. Phenotypic threshold;51
8.3.4;3.4. Recessive and dominant mtDNA mutations;53
8.3.5;3.5. Dominant lethal mtDNA mutations?;54
8.4;4. Clonal Expansion and Age-Dependent Dynamics of mtDNA Mutations;55
8.4.1;4.1. Somatic mtDNA mutations need to be clonal to be relevant to cell physiology;55
8.4.2;4.2. MtDNAs in a cell: A dynamic population of molecules;56
8.4.3;4.3. Clonal expansion via positive selection;57
8.4.4;4.4. Clonal expansions via random genetic drift;59
8.4.5;4.5. Random genetic drift with nonlocal compensatory feedback explains unidirectional expansion of detrimental mutations, ...;61
8.5;5. Effects of Somatic mtDNA Mutations in Aging Tissues;62
8.5.1;5.1. Muscle fibers;62
8.5.2;5.2. Neurons;63
8.5.3;5.3. Colonic crypts;65
8.5.4;5.4. Interplay of clonal expansion and de novo generation of mtDNA mutations;67
8.5.5;5.5. The ``Vicious cycle´´;68
8.6;6. Evolutionary Considerations and Interspecies Comparisons;69
8.6.1;6.1. Is mitochondrial genome too small?;69
8.6.2;6.2. Are somatic mtDNA mutations under longevity-related selective pressure?;70
8.6.3;6.3. MtDNA ``mutator´´ mice: Do they confirm or disprove the mtDNA hypothesis of aging?;71
8.6.4;6.4. Longevity-related sequence traits in mtDNA;72
8.6.5;6.5. Extended human lifespan and growing contribution of somatic mtDNA mutations;73
8.7;Acknowledgments;73
8.8;References;74
9;Chapter Three: Mathematical Models of Mitochondrial Aging and Dynamics;78
9.1;1. Introduction;79
9.2;2. Fundamentals of Mathematical Modeling;80
9.2.1;2.1. Reconstructing networks;82
9.2.2;2.2. Logical models with focus on Boolean modeling;83
9.2.3;2.3. Continuous modeling-The basics of network dynamics described with ordinary differential equations;85
9.2.4;2.4. Simplifications specific to metabolic networks-Flux-balance analysis;90
9.2.5;2.5. Agent-based models;90
9.3;3. Models of Mitochondrial Aging and Dynamics;91
9.3.1;3.1. Early models;91
9.3.2;3.2. Mitochondrial dynamics;94
9.3.3;3.3. Accumulation of deletion mutants;97
9.4;4. Conclusions and Perspectives;101
9.5;References;102
10;Chapter Four: Mitochondrial Dynamics in Aging and Disease;108
10.1;1. Introduction;109
10.2;2. Mitochondrial Trafficking and Localization Within Cells;111
10.2.1;2.1. Localization of mitochondria within cells;111
10.2.2;2.2. Trafficking of mitochondria within cells;112
10.2.2.1;2.2.1. Neurodegenerative disorders related to impaired mitochondrial trafficking;116
10.2.3;2.3. How do mitochondria associate with energy requiring structures within cells?;117
10.3;3. Fusion and Fission Regulate Mitochondrial Size and Functionality;119
10.3.1;3.1. The fusion and fission machinery and its control;120
10.3.1.1;3.1.1. Fission;121
10.3.1.2;3.1.2. Fusion;124
10.3.2;3.2. The physiological significance of fusion and fission;125
10.3.2.1;3.2.1. Ubiquitous fusion and fission;125
10.3.2.2;3.2.2. Fusion and fission as related to aging;128
10.3.2.3;3.2.3. Fusion and fission as related to apoptosis and neuronal degeneration;129
10.3.2.4;3.2.4. Linking trafficking, fusion and fission;130
10.3.2.5;3.2.5. The role of fusion and fission for mtDNA integrity;131
10.4;4. Dynamics of Proteins Within Mitochondrial Membranes and the Matrix;133
10.5;Acknowledgments;135
10.6;References;135
11;Chapter Five: The Retrograde Response: A Conserved Compensatory Reaction to Damage from Within and from Without;148
11.1;1. Introduction;149
11.2;2. The Retrograde Signaling Pathway;150
11.3;3. Consequences of Retrograde Signaling;154
11.4;4. Other Retrograde Responses in Yeast;156
11.5;5. The Retrograde Response and Cell Quality Control;157
11.6;6. Retrograde Response in Other Organisms;159
11.7;7. Evolution of the Retrograde Response as a Cytoprotective Mechanism;161
11.8;Acknowledgment;162
11.9;References;162
12;Chapter Six: Mitochondrial Acetylation and Genetic Models of Parkinson´s Disease;170
12.1;1. Introduction: Longevity Modulation by Nutrient and Bioenergetic Pathways;171
12.2;2. The Central Role of Sirtuins;171
12.3;3. Mitochondrial Deacetylation Effects on Oxidative Stress and Cancer;175
12.4;4. Mitophagy Regulation;176
12.5;5. Mitochondrial Clearance in PD Patient Cells;178
12.6;6. Available Genetic Animal Models for PD-Associated Mitochondrial Pathology;178
12.7;7. Preliminary Findings on Mitochondrial Acetylation in Our PD Mouse Model;179
12.8;8. The Prediction of PD;189
12.9;9. Conclusions;191
12.10;Acknowledgments;191
12.11;References;191
13;Chapter Seven: Mitochondrial Dysfunction: Cause and Consequence of Alzheimer´s Disease;198
13.1;1. Brain Aging: The Role of OXPHOS and ROS;199
13.2;2. Mitochondrial Dysfunction in Alzheimer´s Disease;201
13.3;3. Aß and Tau-A Deleterious Duo for Mitochondrial Function;203
13.4;4. Mitochondrial-Derived ROS Induce Aß Generation-Focus on Complexes I and III;207
13.5;5. Interplay Between Aging and AD: The Balance Between Synergistic Dysfunction and Functional Compensation;208
13.6;6. Pharmacological Strategies to Improve Mitochondrial Function;210
13.7;7. Antioxidants, Flavonoids, Polyphenols, and Ginkgo;212
13.8;8. Metabolic Enhancer;214
13.9;9. Dimebon;214
13.10;10. Conclusion and Further Perspective;215
13.11;References;216
14;Chapter Eight: Mitochondria in Cancer: Why Mitochondria Are a Good Target for Cancer Therapy;226
14.1;1. Mitochondria in Malignant Cells-Culprits or Victims?;226
14.2;2. Mitochondria as Targets for Anticancer Therapy;230
14.3;3. Conclusions and Perspectives;236
14.4;Acknowledgments;237
14.5;References;237
15;Chapter Nine: Estrogen and Mitochondria Function in Cardiorenal Metabolic Syndrome;244
15.1;1. Introduction;245
15.2;2. Mitochondria in CRS;248
15.2.1;2.1. Mitochondria structure and function;248
15.2.2;2.2. Risk factors in mitochondria function;250
15.2.3;2.3. Mitochondria dysfunction in CRS;251
15.3;3. Estrogen and Mitochondrial Function;252
15.3.1;3.1. Estrogen, ERs, and their signaling pathways;252
15.3.2;3.2. Roles of estrogen in mitochondria function;254
15.4;4. Abnormalities in Estrogen Signaling Promotes Development of the CRS;256
15.4.1;4.1. Estrogen and ERs in CVD;256
15.4.2;4.2. Estrogen regulates glucose homeostasis and IR;258
15.4.3;4.3. Estrogen regulates lipogenesis and lipolysis;259
15.4.4;4.4. Estrogen regulates inflammatory responses;259
15.5;5. Conclusions;260
15.6;Acknowledgments;261
15.7;References;261
16;Chapter Ten: Advances in Development of Rechargeable Mitochondrial Antioxidants;266
16.1;1. Introduction;267
16.2;2. Ischemia-Reperfusion;268
16.3;3. Age-Dependent Disorders;269
16.4;4. Liver Protection;270
16.5;5. Inflammation;271
16.6;6. Neurodegenerative Diseases;273
16.7;7. Ophthalmic Diseases;275
16.8;8. Novel Mitochondrial Antioxidants;277
16.9;9. Mild Uncoupling;277
16.10;References;278
17;Index;282
18;Color Plate;291

Leseproben

Chapter Two Mitochondrial DNA Mutations in Aging
Konstantin Khrapko*; Doug Turnbull†    * Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
† LLHW Centre for Ageing and Vitality, Newcastle University, Newcastle, United Kingdom Abstract
The relationship of mitochondrial DNA mutations to aging is still debated. Most mtDNA mutations are recessive: there are multiple copies per cell and mutation needs to clonally expand to cause respiratory deficiency. Overall mtDNA mutant loads are low, so effects of mutations are limited to critical areas where mutations locally reach high fractions. This includes respiratory chain deficient zones in muscle fibers, respiratory-deficient crypts in colon, and massive expansions of deleted mtDNA in substantia nigra neurons. mtDNA “mutator” mouse with increased rate of mtDNA mutations is a useful model, although rates and distribution of mutations may significantly deviate from what is observed in human aging. Comparison of species with different longevity reveals intriguing longevity-related traits in mtDNA sequence, although their significance is yet to be evaluated. The impact of somatic mtDNA mutations rapidly increases with age, so their importance is expected to grow as human life expectancy increases. Keywords Aging Mutations Mitochondrial DNA Clonal expansion Evolution of aging 1 Introduction: The Different Faces of the Mitochondrial Theory of Aging
Mitochondrial involvement in aging was proposed over 30 years ago by Denham Harman, based on his original theory that aging is caused by the accumulation of damage resulting from reactive oxygen species (ROS).1 ROS are the inevitable by-products of normal cellular processes, most notably the process of oxidative phosphorylation, which is the primary function of the mitochondrion. Harman noted that as a major source of ROS, mitochondria should also be its major target.1 Hence, as the part of the cell most vulnerable to ROS, mitochondria could play the role of the “aging clock,” the limiting aging component of the system. Later, Linnane and others2 specifically implied accumulating mitochondrial DNA (mtDNA) mutations (as opposed to general damage, which usually means also chemical modifications of DNA and other macromolecules) as the main culprit in aging. The logic is that mitochondria are renewable organelles. Some of them grow, replicate their DNA, and divide. Other mitochondria are destroyed and replaced by newly divided ones. This means that all their damaged components are constantly replaced by newly synthesized ones. The only part that saves the record of past damage despite this turnover is the sequence of mtDNA. Indeed, mtDNA mutations once they arise are replicated and faithfully transmitted to the daughter mitochondria. This supports the hypothesis that accumulation of mtDNA mutations is one of the “primary” aging processes. The significance of mtDNA mutations for aging is also corroborated by a few other observations, of which most notable is the presence in old tissues, muscle, brain, and colon in particular, of cells that are deficient in mitochondrial function caused by mtDNA mutations (Fig. 2.1). Figure 2.1 Examples of mitochondrial defects caused by mtDNA mutations in aged tissues. Cells lacking an mtDNA-encoded enzyme of electron transport chain, cytochrome-c oxidase are colored blue (blue color is visible only in the colored image) by special staining. (A) Skeletal muscle, (B) pigmented neurons of the substantia nigra (asterisks mark the deficient cells), and (C) clolon crypts. Of note, mitochondrial mutational hypothesis of aging should be distinguished from a few other mitochondrial hypotheses of aging, which do not explicitly refer to mtDNA mutations (genetic damage), but rather to chemical damage, such as oxidation, cross-links, and other covalent modification of macromolecules (including DNA). The various concepts are not mutually exclusive and all may very well have their share in the aging process. For example, “mitochondrial-lysosomal axis” theory of aging3 maintains that in aged cells, accumulating oxidated cellular waste (primarily damaged mitochondria) “chocks” cellular autophagy systems. This further hampers turnover of damaged mitochondria creating a self-accelerating loop that eventually cumulates in dysfunctional cells or cell death. Another, more traditional “mitochondrial free radical theory of aging” (Chapter 1), postulates that aging is caused by accumulating oxidative damage, which does not necessarily involve a self-accelerating component. In this view, aging can be caused by a constant rate of oxidative damage. In this theory, while mitochondria are also considered a critical component, the main source and main target of oxidative damage, mtDNA mutations do not play a central role in this theory, they are just a part of damage. Despite its attractiveness, the idea that mutations in mtDNA cause at least some aspects of aging remains controversial. Mitochondrial defects in aging tissues (Fig. 2.1) are yet to be convincingly related to age-related pathologies. To make the case of mtDNA mutations even more challenging, there are a few examples where artificially increased number of somatic mtDNA mutations in genetically engineered mice does not result in accelerated aging,4 implying that at least some types mtDNA mutations are not involved in aging. Furthermore, controversy is fueled by the difficulties in accurately measuring of the fraction of mutant molecules. Some estimates yield rather unimpressively low overall fractions of mtDNA mutations, which seem to challenge the idea that these mutations may be of any significance. High estimates by other methods are sometimes perceived as gross overestimates.78 To make things even more complicated, to estimate the functional impact of mtDNA mutations, one needs to know, in addition to overall mutant fraction, the detailed cell-to-cell distribution of mutations. This is because mutant mtDNA tend to affect cellular physiology only once they reach certain percentage within the mtDNA population of each individual cell, called the physiological threshold (Section 3). Here, we will review the evidence in support of the mtDNA mutational hypothesis of aging, which ranges from data on the detailed cell-by-cell distribution of mtDNA mutations to the inverse correlation of the number of repeats in mtDNA sequence and species’ longevity. 2 Mitochondria, mtDNA, and mtDNA Mutations
2.1 Mitochondrial biology and mtDNA
Mitochondria are subcellular organelles responsible for generation of ATP, the cell's universal energy carrier, in a process of oxidative phosphorylation. This process is performed by a set of five multisubunit enzyme complexes (I, II, III, IV, and V) called the respiratory chain (RC), which are located on the inner membrane of the mitochondrion (for illustration see Ref. 5). Depending on the metabolic requirement of the cell, the number of mitochondria can vary markedly. In the majority of cells, mitochondria appear as a thread-like network throughout the cell and are constantly undergoing fission and fusion, a process that seems to be very important in terms of physiology and turnover of mitochondria.6,7 Mitochondria carry their own genome, i.e., a small (about 16,500 base pairs in animals) circular DNA molecule, which is replicated by the mtDNA polymerase gamma. Animal mtDNA encodes 13 polypeptides, which are subunits of all but one (complex II) of the RC complexes, as well as mitochondrial 22 tRNA and 2 rRNA.8 All other subunits of the RC enzymes (~ 80 of them) are encoded in the nuclear genome,5 as are the rest of several hundred mitochondrial proteins that are located in mitochondria but are not directly involved in the RC. Of note, outside the animal kingdom, mtDNA types are rather diverse.9 MtDNA is maternally inherited in mammals since all the mitochondria from the sperm are destroyed on entry into the ovum. MtDNA is present in multiple copies in all cells. The number of copies of mtDNA varies markedly between cells, with tissues with high energy requirements, such as brain, heart, and skeletal muscle, harboring the largest numbers of mitochondrial genomes. MtDNA is believed to be organized into “nucleoids,” i.e., compact nucleoprotein particles containing from one to a few mtDNA molecules. The exact composition, structure, and function of nucleoids are under intense investigation.10 2.2 mtDNA mutations
The mitochondrial genome principally suffers from two types of mutations: point mutations and large genome rearrangements, of which most studied are deletions, i.e., loss of large portions of the genome (from a few hundred base pairs to almost the entire mitochondrial genome). There are several possible sources of mtDNA mutations, which can be broadly classified into spontaneous errors and damage-induced mutations. Spontaneous polymerase errors result from inherent polymerase infidelity. For example, an incorrect nucleotide may be inserted opposite to a normal nucleotide of the DNA template to generate base substitution. DNA damage is the other source of mutations. In the simplest case, DNA polymerase may be prompted to insert...