Mitochondria have been pivotal in the development of some of the most important ideas in modern biology. Since the discovery that the organelle has its own DNA and specific mutations were found in association with neuromuscular and cardiovascular diseases and with aging, an extraordinary number of publications have followed, and the term mitochondrial medicine was coined. Furthermore, our understanding of the multiple roles that mitochondria play in cardiac cell homeostasis opened the door for intensive experimentation to understand the pathogenesis and to find new treatments for cardiovascular diseases.
Besides its role in adenosine triphosphate generation, mitochondria regu-late a complex network of cellular interactions, involving:
- generation and detoxification of reactive oxygen species, including superoxide anion, hydrogen peroxide, and hydroxyl radical;
- maintenance of the antioxidant glutathione in a reduced state and adequate level of mitochondrial matrix superoxide dismutase;
- cytoplasmic calcium homeostasis, particularly under conditions of cellular calcium loading;
- transport of metabolites between cytoplasm and matrix;
- both programmed (apoptosis) and necrotic cell death; and
- cell growth and development. It is therefore not surprising that this organelle has come to be the center stage in many current investigations of cardiovascular diseases, aging, and agingrelated disease.
Concomitant with these advances, an impressive effort is underway for the development of new tools and methodologies to study mitochondrial structure and function, including powerful ways to visualize, monitor, and alter the organelle function to assess the genetic consequences of these perturbations.
Because the heart is highly dependent for its function on oxidative energy that is generated in mitochondria - primarily by fatty acid p oxidation, respiratory electron chain, and oxidative phosphorylation (OXPHOS) - it is understandable that defects in mitochondrial structure and function can be found in association with cardiovascular diseases.
Abnormalities in the organelle structure and function are being increasingly reported in association with conditions such as dilated and hypertrophic cardiomyopathy, cardiac conduction defects and sudden death, ischemic and alcoholic cardiomyopathy, myocarditis, and neuromuscular diseases associated with cardiac disease and aging. Some of the mitochondrial abnormalities may have a genetic basis (e.g., mitochondrial DNA changes might lead to abnormal OXPHOS, and fatty acid oxidation defects might be due to specific nuclear DNA mutations), while other abnormalities may be due to a more sporadic or environmental cardiotoxic insult or may not yet be characterized. To understand the role that mitochondria play in cardiovascular disease, we discuss the biogenesis and function of cardiac mitochondria during normal growth, development, and aging. Within this context, we then examine the interaction and characterization of mitochondria and mitochondrial abnormalities in cardiac diseases, their diagnosis, therapeutic options currently available, future directions for research, and new frontiers in treatment. While aberrations in the bioenergetic function of the mitochondria are frequently related to cardiac dysfunction, the specific defect causing the bioenergetic abnormalities often resides in a non bioenergetic pathway (e.g.,signaling between the mitochondria and nucleus) or in the overall mitochondrial biogenesis or degradation pathways. Understanding these pathways and the effects that mitochondrial defects have in cardiac pathology is extremely important in establishing the diagnosis and treatment of mitochondrial based cardiac diseases.
As mitochondria's role in the field of cardiology is strengthened and as research on the multiple functions of this organelle continues its expansion, the time seems appropriate for a book that may integrate known facts, what is developing and what will be known in the near future. In addition to providing a recount of past discoveries, the book deals with areas that are of emerging interest to researchers and clinicians, eyeing potential alternatives that may improve currently available therapies and interventions in the management of cardiovascular diseases in general and the cardiovascular pathology of aging in particular.
Contents Chapter 1. An Introduction to Mitochondria and the Heart
- Overview
- What are mitochondria?
- How to study mitochondria: New and old
- Mitochondrial bioenergetics
- Mitochondrial biogenesis
- Cardiac mitochondrial changes during cardiac growth and development
- Mitochondria: the primary site of ROS generation and also a critical target of its damaging effects
- Mitochondrial dysfunction in cardiovascular disease
- Defects in mtDNA
- Defects in nuclear-DNA encoded mitochondrial proteins
- Myocardial ischemia and ETC
- Apoptosis and cell death
- Animal models of mitochondrial-associated cardiovascular disease
- Diagnosis and treatment of mitochondrial-based cardiac diseases
- The road ahead
Chapter 2. Mitochondrial Bioenergetics in the Heart
- Overview
- Introduction
- Complex I (NADH-ubiquinone oxidoreductase)
- Enzyme structure
- Complex II (Succinate-ubiquinone oxidoreductase)
- Complex III (Ubiquinol-cytochrome c oxidoreductase)
- The Q cycle and bcl function
- Complex IV (Cytochromec oxidase)
- COX enzyme structure
- COX subunit gene structure and expression
- COX activity regulation
- Complex V (F0-Fi ATPase; ATP synthase)
- Subunit composition, structure, and function
- ATP synthase defects and related pathologies
- Other enzymes bioenergetics
- Adenine nucleotide translocator (ANT)
- ANT structure
- ANT regulation in the heart
- ANT genes and their expression
- ANT dysfunction plays a key role in cardiac pathology
- Creatine kinase
- Structure
- Creatine kinase and the heart
- PDH and the TCA (Krebs) cycle
- Overall regulation of mitochondrial bioenergetic in the heart
- Supply and demand, substrates, and oxygen and ATP-ADP levels
Chapter 3. Heart Mitochondrial Biogenesis
- Overview
- Introduction
- Structure of mtDNA
- MtDNA Function
- Replication
- Regulation of mtDNA replication
- Mitochondrial transcription and RNA processing
- Regulation of mitochondrial transcription and processing
- Mitochondrial translation
- Mitochondrial ribosomes
- Initiation and elongation of translation
- Mitochondria DNA repair
- Nuclear participation in mitochondrial biogenesis
- Nuclear regulatory proteins and coordination of transcriptional events
- Hormones affecting both mitochondrial and nuclear transcription
- Mitochondria import and assembly of proteins
- Relevance of mitochondrial biogenesis
Chapter 4. ROS Generation, Antioxidants, and Cell Death
- Overview
- Introduction
- The significance of ROS
- Generation of ROS
- Negative effect of ROS
- Antioxidant defense
- Role of ROS in cell signaling
- ROS and cardiac pathology
- ROS and apoptosis
- Apoptosis and cell death
- Myocardial apoptosis
Chapter 5. Myocardial Ischemia and Cardioprotection
- Overview
- Introduction
- Mitochondrial dysfunction in myocardial ischemia
- Oxidation-phosphorylation decline in ischemia
- Myocardial ischemia and oxidative stress
- Myocardial ischemia and mitochondrial calcium flux
- Gene expression
- Reperfusion
- Cardioprotection
- Ischemic cardioprotection
- Cascade of mitochondrial events in IPC
- Signaling pathways
- Adenosine and other ligands
- Activation and translocation of PKC as a pivotal signaling event in the genesis of IPC and CP
- Reactive oxygen species
- Cardioprotection: An emerging field
- Early and late IPC pathways
- Potential applications to clinical medicine
Chapter 6. Mitochondria Dysfunction in Cardiomyopathy and Heart failure
- Overview
- Introduction
- Mitochondria are the major source of bioenergy in the cardiac cell
- What is the evidence for myocardial dependency on mitochondrial function?
- Mitochondrial dysfunction and cardiomyopathy: Support from human studies
- Clinical evidence of nuclear mutations in mitochondrial components
- Contribution of transgenic models to the study of mitochondria in heart dysfunction
- Evidence from animals models that mitochondrial bioenergetic enzymes play a critical role in HF
- Mitochondrial dysfunction and other cellular pathways in cardiomyopathy
- Mutations in contractile/ sarcomere proteins and mitochondrial function
- Mitochondrial function and cardiac hypertrophy
- Calcium signaling and mitochondrial function in HF
- Mitochondrial function and apoptosis in HF
- What events occurring in HF are truly tissue-specific?
- Future prospects
Chapter 7. Fatty Acid and Glucose Metabolism in Cardiac Disease
- Overview
- Introduction
- Role of fatty acids and their metabolism in the normal cardiomyocyte: Structural and regulatory roles in cardiac cell membranes
- Fatty acid transporters and glucose carriers
- B ioenergetics of FAO
- Cellular location of FAO and glucose oxidation
- The effect of disorders of fatty acid and glucose metabolism on cardiac structure/ function
- Secondary effects on mitochondrial fatty acid (3-oxidation: Relationship to mitochondrial respiration and OXPHOS
- Fatty acid metabolism defects and their association with cardiomyopathy and arrhythmias
- Cardiomyopathy
- Arrhythmias and conduction defects
- Fatty acids, glucose, and cardiac apoptosis
- Abnormalities in mtDNA and their association with both diabetes and cardiomyopathy
- Molecular players in fatty acid-related cardiac diseases; modulation of gene expression
- MCAD
- VLCAD
- CPT-II
- MTP
- PPAR
- Peroxisome proliferator-activated receptor y coactivator (PGC- l a )
- Animal models of defective fatty acid metabolism and cardiac failure
- Advances in diagnostics and treatment of fatty acid/cardiac disease
Chapter 8. Mitochondria in Pediatric Cardiology
- Overview
MlTOCHONDRIAL CARDIOMYOPATHY
- Introduction
- Diagnosis
- Clinical signs
- Histological and electron microscopic (EM) analysis
- Biochemical analysis
- MtDNA analysis
- Mitochondrial tRNA mutations
- Mitochondrial structural gene mutations
- ATP synthase (ATPase 6)
- Cytochrome b (cytb)
- Mutations in COX and ND subunits
- MtDNA depletion
MITOCHONDRIA AND CONGENITAL HEART DEFECTS (CHD)
- Structural and functional cardiac defects
- Cardiac arrhythmias
- Other congenital cardiomyopathies with mitochondrial defects
- Congenital heart defects and mitochondrial respiration
- Conclusions
Chapter 9. Mitochondria and the Aging Heart
- Overview
- Introduction
- Bioenergetics and gene expression in the aging heart
- Mitochondrial function and gene expression in the aging heart
- ROS in the aging heart
- Mitochondrial DNA damage in the aging heart
- Rat model of cardiac aging: Defects in ETC
- Gene expression
- DNA copy number and damage analysis
- Comments
- On mitochondrial dysfunction
- On mitochondrial DNA damage
- On gene expression of mitochondrial stress proteins and cellular programming
- On mitochondrial PT pore
- Conclusions
- Potential approaches to reverse mitochondrial dysfunction in the aging heart
Chapter 10. Heart Mitochondria Signaling Pathways
- Overview
- Introduction
- Mitochondrial abnormalities, signaling defects, and myocardial disease
- Mitochondrial signaling in myocardial ischemia and cardioprotection
- Mitochondrial signaling and myocardial hypertrophy
- Signaling the mitochondria: Key players
- Nuclear gene activation
- Protein kinases
- Calcium signaling
- Mitochondrial receptors
- Signals of survival and stress impact heart mitochondria
- Survival signals and apoptosis
- Stress signals
- Metabolic signals
- Future prospects: Therapeutic targets and directions
- The essential role played by mitochondriain in cytoprotective signaling and CP
- Mitochondrial metabolic intermediates
- Summary
Chapter 11. Treatment of Mitochondrial-Based Cardiac Diseases: Targeting the Organelle
- Overview
- Introduction
- Treatment of respiratory and metabolic defects
- Use of antioxidants
- Treatment of FAO disorders, arrhythmias, and CHF
- Cardioprotective agents
- New approaches in treatment
- Gene therapy in cardiovascular diseases
- Mitochondria and gene therapy
- Targeting mitochondria using nucleic acids
- Targeting mitochondria using bioactive compounds
12. Future Frontiers in Mitochondrial Cardiac Biology
- Overview
- Introduction
- Disease gene identification: Diagnostic application
- Modifying factors, Epigenetics, and SNPs
- Animal models of mitochondrial-based heart disease
- Cellular engineering
- Applications of stem cells in mitochondrial defects and toxicology
Glossary
Index
Book Details
- Hardcover: 400 pages
- Publisher: Springer; 1 edition (May 5, 2005)
- Language: English
- ISBN-10: 0387255745
- ISBN-13: 978-0387255743
- Product Dimensions: 9.3 x 6.3 x 1.3 inches
List Price: $219.00