Mitochondrial Metabolism An Approach For Disease Management

Mitochondrial Metabolism: An Approach for Disease Management covers mitotherapy from three combined perspectives, Pharmacology, Toxicology and Biochemistry. After an introduction from world-renowned experts, the book's chapters cover the balancing role in reduction/oxidation mitochondria play, mitochondria as targets for therapeutics through its metabolism, mitochondrial contributions to the cell death process, mitochondrial response to environmental toxicants, the mitochondrial role in aging, the impact of calorie restrictive diets, new advances in the identification of altered mitochondria associated signaling pathways in carcinogenesis, and much more. This book provides bioscientists new horizons to realize the importance of mitochondria in present-day research on therapies dealing with mitochondria associated chronic diseases, including diabetes, cancer and neurodegenerative disorders. Details the significant role of mitochondria in chronic diseases Presents new insights on the targeting of mitochondria for therapeutic purposes Includes updated results on mitotherapy and other mitochondria-oriented therapies

This text covers the basic principles of mitochondrial dynamics in cardiovascular medicine, with particular emphasis on their functional roles in physiology and disease. The book will include articles pertaining to mitochondrial fitness on a global basis, providing therefore an update on the progress made in several aspects in the field. Thus, it will assist scientists and clinicians alike in furthering basic and translational research. Organized in sections focusing on: basic science, mitochondrial dysfunction in cardiac disorders, in vascular disorders, in metabolic disorders, in kidney disease, therapeutic challenges and options, this essential volume fills imperative gaps in understanding and potentially treating several cardiovascular disorders.

The book addresses controversies related to the origins of cancer and provides solutions to cancer management and prevention. It expands upon Otto Warburg's well-known theory that all cancer is a disease of energy metabolism. However, Warburg did not link his theory to the "hallmarks of cancer" and thus his theory was discredited. This book aims to provide evidence, through case studies, that cancer is primarily a metabolic disease requring metabolic solutions for its management and prevention. Support for this position is derived from critical assessment of current cancer theories. Brain cancer case studies are presented as a proof of principle for metabolic solutions to disease management, but similarities are drawn to other types of cancer, including breast and colon, due to the same cellular mutations that they demonstrate.

Breast cancer is the most common cancer affecting women today. Although many advancements in treatment have been made, breast cancer is still the second leading cause of cancer-related deaths in Canadian women- demonstrating the need for a greater understanding of this complex disease. The re-wiring of cellular metabolism represents an important alteration in cancer cells that is needed to support their exponential growth. In addition, each step of cancer progression to metastatic disease presents novel bioenergetic and biosynthetic challenges, requiring metabolic adaptations within the cancer cells. Despite increasing knowledge about cancer progression, the characterization of such metabolic changes is incomplete. Classically, the Warburg effect states that cancer cells adopt an extremely glycolytic phenotype, taking up large amounts of glucose for rapid ATP production. Over the years this has been attributed to dysfunctional mitochondria in cancer cells. More recently however it is understood that mitochondria play vital roles in cancer progression and support various cellular metabolic rearrangements in cancer cells. In this work, we show a novel methodology to study isolated functional mitochondria from cancer cells in order to obtain insights into their intrinsic properties- to ultimately understand their contribution to cancer progression. Using this approach, we investigate and characterize the mode of action of metformin, the most commonly prescribed drug for the treatment of type II diabetes, which is being evaluated for use in cancer treatment. We show that metformin directly targets mitochondria and deregulates cellular bioenergetics and metabolism in cancer cells. Lastly, we investigate PGC-1, a central regulator of cellular and mitochondrial metabolism, and its role in breast cancer progression, metastasis and response to bioenergetic drugs. Overall, we elucidate the role of mitochondrial metabolism on cancer cell progression and metastasis as well as shed light on the effects of metformin on these processes.

The heart has a very high energy demand but very little energy reserves. In order to sustain contractile function, the heart has to continually produce a large amount of ATP. The heart utilizes free fatty acids mainly and carbohydrates to some extent as substrates for making energy and any change in this energy supply can seriously compromise cardiac function. It has emerged that alterations in cardiac energy metabolism are a major contributor to the development of a number of different forms of heart disease. It is also now known that optimizing energy metabolism in the heart is a viable and important approach to treating various forms of heart disease. Cardiac Energy Metabolism in Health and Disease describes the research advances that have been made in understanding what controls cardiac energy metabolism at molecular, transcriptional and physiological levels. It also describes how alterations in energy metabolism contribute to the development of heart dysfunction and how optimization of energy metabolism can be used to treat heart disease. The topics covered include a discussion of the effects of myocardial ischemia, diabetes, obesity, hypertrophy, heart failure, and genetic disorders of mitochondrial oxidative metabolism on cardiac energetics. The treatment of heart disease by optimizing energy metabolism is also discussed, which includes increasing overall energy production as well as increasing the efficiency of energy production and switching energy substrate preference of the heart. This book will be a valuable source of information to graduate students, postdoctoral fellows, and investigators in the field of experimental cardiology as well as biochemists, physiologists, pharmacologists, cardiologists, cardiovascular surgeons and other health professionals.

Texts on inborn errors of metabolism (IEMs) have traditionally focused on classical biochemistry, clinical presentation, and standard treatment approaches. Inborn Errors of Metabolism is an expansion on this model, one that establishes an innovative pathway approach and provides a new authority on this family of disease. Alongside the standard cadre of molecular and clinical underpinnings, this volume includes coverage of newborn screenings and an overarching treatment of IEMs as complex diseases -- how basic alterations can lead to complex secondary and tertiary effects in metabolism that contribute to increasingly recognized natural histories of disease.

"Breast cancer is the most common cancer affecting women today. Although many advancements in treatment have been made, breast cancer is still the second leading cause of cancer-related deaths in Canadian women- demonstrating the need for a greater understanding of this complex disease. The re-wiring of cellular metabolism represents an important alteration in cancer cells that is needed to support their exponential growth. In addition, each step of cancer progression to metastatic disease presents novel bioenergetic and biosynthetic challenges, requiring metabolic adaptations within the cancer cells. Despite increasing knowledge about cancer progression, the characterization of such metabolic changes is incomplete. Classically, the Warburg effect states that cancer cells adopt an extremely glycolytic phenotype, taking up large amounts of glucose for rapid ATP production. Over the years this has been attributed to dysfunctional mitochondria in cancer cells. More recently however it is understood that mitochondria play vital roles in cancer progression and support various cellular metabolic rearrangements in cancer cells. In this work, we show a novel methodology to study isolated functional mitochondria from cancer cells in order to obtain insights into their intrinsic properties- to ultimately understand their contribution to cancer progression. Using this approach, we investigate and characterize the mode of action of metformin, the most commonly prescribed drug for the treatment of type II diabetes, which is being evaluated for use in cancer treatment. We show that metformin directly targets mitochondria and deregulates cellular bioenergetics and metabolism in cancer cells. Lastly, we investigate PGC-1, a central regulator of cellular and mitochondrial metabolism, and its role in breast cancer progression, metastasis and response to bioenergetic drugs. Overall, we elucidate the role of mitochondrial metabolism on cancer cell progression and metastasis as well as shed light on the effects of metformin on these processes." --

Mitochondrial dysfunction has emerged as a common cause of peripheral neuropathies. While the role of neuronal and axonal mitochondria in peripheral nerve disease is well appreciated, whether Schwann cell (SC) mitochondrial deficits contribute to peripheral neuropathies is unclear. Greater insight into the biology and pathology of SC mitochondrial metabolism could be relevant to the treatment of peripheral neuropathies, particularly because SCs critically support axonal stability and function as well as promote peripheral nerve regeneration. The present thesis investigates the contribution of SC mitochondrial deficits to disease progression in peripheral neuropathies as well as the gene regulatory network that drives the SC regenerative response after injury and in disease states. We describe the generation and characterization of the first mouse model useful in directly interrogating the contribution of SC mitochondrial dysfunction to peripheral neuropathy. These mice (Tfam-SCKOs) were produced through the tissue-specific deletion of the mitochondrial transcription factor A gene (Tfam), which is required for mtDNA transcription and replication. Interestingly, induction of SC-specific mitochondrial dysfunction did not affect SC survival; instead, these deficits resulted in a severe, progressive peripheral neuropathy characterized by extensive axonal degeneration that recapitulated critical features of human neuropathy. Mechanistically, we demonstrated that SC mitochondrial dysfunction activates a maladaptive integrated stress response and causes a shift in lipid metabolism away from new lipid biosynthesis towards increased lipid oxidation. These alterations in lipid metabolism caused the early depletion of key myelin lipid components as well as a dramatic accumulation of acylcarnitine lipid intermediates. Importantly, release of acylcarnitines from SCs was toxic to axons and induced their degeneration. Our results show that normal mitochondrial function in SCs is essential for maintenance of axonal survival and normal peripheral nerve function, suggesting that SC mitochondrial dysfunction contributes to human peripheral neuropathies. Moreover, our work identifies alterations in SC lipid metabolism and the accumulation of toxic lipid intermediates as novel mechanisms driving some of the pathology in peripheral neuropathies associated with mitochondrial dysfunction. Tfam-SCKO mice showed a severe deficiency in their ability to remyelinate peripheral nerve axons after injury. To gain insight into the highly orchestrated process of SC-mediated support of axonal regeneration, we also investigated the transcriptional and post-transcriptional gene regulatory program that drives the SC regenerative response. We profiled the expression of SC microRNAs (miRNAs) after peripheral nerve lesions as well as characterized the injury response of SCs with disrupted miRNA processing and showed that SC miRNAs modulated the injury response largely by targeting positive regulators of SC dedifferentiation/proliferation. SC miRNAs cooperated with transcriptional regulators to promote rapid and robust transitions between the distinct differentiation states necessary to support nerve regeneration. Moreover, we identified miR-34a and miR-140 as regulators of SC proliferation and myelination. We then used a novel computational approach to infer the gene regulatory network involved in this SC injury response and gain insight on cooperative regulation of this process by transcription factors and miRNAs. Together, the results described in the present thesis represent a significant increase in our understanding of how mitochondrial abnormalities specifically in SCs contribute to clinical impairment in patients with peripheral neuropathy. Moreover, the mechanistic characterization of lipid metabolism abnormalities in SCs following mitochondrial dysfunction elucidates potentially important therapeutic targets. Finally, our analysis of the transcriptional and post-transcriptional gene regulatory network involved in the SC regenerative response also provides valuable insight that could be harnessed to help restore normal nerve function in patients with peripheral neuropathy.

As a leading reference on pediatric cardiology and congenital heart disease, Anderson's Pediatric Cardiology provides exhaustive coverage of potential pediatric cardiovascular anomalies, potential sequelae related to these anomalies, comorbidities and neurodevelopmental problems, and current methods for management and treatment. The fully revised 4th Edition addresses significant and ongoing changes in practice, including recent developments in fetal, neonatal, and adult congenital heart conditions as well as expanded content on intensive care, nursing issues, and societal implications. The outstanding illustration program provides superb visual guidance, and is now supplemented with a remarkable collection of more than 200 professionally curated, author-narrated videos. Offers authoritative, long-term coverage of a broad spectrum of cardiology conditions ranging from fetal development to age 21, including congenital heart disease, adult congenital heart disease (ACHD), acquired heart disease, cardiomyopathies, and rhythm disturbances. Features exceptionally detailed and original drawings by Dr. Robert Anderson and Diane Spicer, including over 850 anatomic, photographic, imaging, and algorithmic figures, and incorporating new images using virtual dissections of 3D datasets obtained in living patients. Contains new chapters on quality improvement in congenital heart disease, models of care delivery, neurocognitive assessment and outcomes, psychosocial issues for patients and families, ethics, nursing implications, acute and chronic renal complications, and telemedicine. Offers a completely new section on fetal imaging and management. Provides a new focus on patient and family-centered care with expert advice on how to communicate difficult diagnoses to patients and families. Features new integration of nursing content into all disease-specific chapters, as well as updated content on genetics, congenital heart disease and follow-up, and new imaging modalities. Contains chapters on new and emerging topics such as MRI and Quantifying the Fetal Circulation in Congenital Cardiac Disease; Congenital Anomalies of the Coronary Arteries; and The Global Burden of Pediatric Heart Disease and Pediatric Cardiac Care in Low- and Middle-Income Countries. Shares the experience and knowledge of an international team of multidisciplinary experts in medicine and advanced practice nursing.

Nearly a century of scientific research has revealed that mitochondrial dysfunction is one of the most common and consistent phenotypes of cancer cells. A number of notable differences in the mitochondria of normal and cancer cells have been described. These include differences in mitochondrial metabolic activity, molecular composition of mitochondria and mtDNA sequence, as well as in alteration of nuclear genes encoding mitochondrial proteins. This book, Mitochondria and Cancer, edited by Keshav K. Singh and Leslie C. Costello, presents thorough analyses of mitochondrial dysfunction as one of the hallmarks of cancer, discusses the clinical implications of mitochondrial defects in cancer, and as unique cellular targets for novel and selective anti-cancer therapy.

Over the past two decades, due to dramatic advances in molecular and cell biology, biochemistry, and genetics, our view on mitochondria as a relatively static cellular powerhouse has changed radically. We now know that these organelles play a critical role in the normal and in the damaged heart. Written by Dr. José Marín-García, Director of the Molecular Cardiology and Neuromuscular Institute, Mitochondria and Their Role in Cardiovascular Disease brings readers up- to-date on the many significant advances in the field of mitochondrial cardiovascular medicine. The book begins with a general introduction to mitochondria, followed by laboratory methods to study the structure and function of the organelle, regulation of replication and biogenesis, and the mechanisms and functional consequences of mitophagia and mitochondrial dynamics. Subsequent chapters deal with mitochondrial oxidative stress and the role that the organelle plays in cell signaling and cell death. Discussions will be undertaken on the biochemistry of mitochondrial cell signaling, including the nature of the proteins engaged in these processes, many of them only recently discovered. Later chapters examine the role of mitochondria and mitochondrial abnormalities in cardiovascular diseases, including their diagnosis, therapeutic options currently available, animal models of mitochondrial disease, and new frontiers in mitochondria cardiovascular medicine, including areas of research that are relatively new or developing, such as proteomics, next generation sequencing, and systems biology.

Mitochondrial dysfunction is increasingly being recognized as the basis of a wide variety of human diseases. Providing an authoritative update on our current knowledge of mitochondrial medicine, this text draws together world authorities from various fields to present general therapeutic strategies, as well as the treatments presently available in different specialties - thus making it essential reading for clinicians involved with the management of patients with mitochondrial diseases. A unique work, this text covers a range of specialties, including cardiology, ophthalmology, otology, nephrology, gastroenterology, hematology-oncology, and reproductive medicine, and does not focus exclusively on the more commonly known neurologic conditions. An accessible, user-friendly text, it also presents translational concepts of mitochondrial biogenesis and genetics in vignettes related to specific questions raised by the disease under discussion, rather than concentrating on basic science, which can often intimidate clinicians. This pioneering work is primarily directed to a clinical audience who are interested in the diverse and diagnostically challenging clinical presentations of mitochondrial diseases and their pathophysiology.

This new volume provides a plethora of new information about potential medicinal herbs and their usefulness in treating diabetes and neurological diseases. Most large multinational companies are interested and engaged in the commercialization of herb-based formulations, and consumers continue to seek natural-based therapies. Herbs for Diabetes and Neurological Disease Management provides insight into plant-based novel molecules targeted for diabetes and neurological disorders. It looks at a selection of herbs that have proven effective in the management of diabetes and neurological disorders, including migraine, epilepsy, memory disorders, depression, and more. Divided into ten chapters focusing on diabetes and its macro- and microvascular complications (migraine, epilepsy, memory disorders, depression and other neuropsychiatric disorders), this book is structured to provide a source of reliable information and enrich the knowledge of readers. Each chapter briefly explains the epidemiology and pathophysiology of the disease state and the possible role of herbal drugs in the prevention of the particular disease. The reported pharmacological activities and possible mechanism of action of herbal drugs are also discussed in detail, which makes this book informative and unique. This new volume will be a reliable reference complementing the substantial information on the use of herbal drugs in diabetes and neurological disorders that serve as the pillars of drug discovery and development.

Functional Metabolism of Cells is the first comprehensive survey of metabolism, offering an in-depth examination of metabolism and regulation of carbohydrates, lipids, and amino acids. It provides a basic background on metabolic regulation and adaptation as well as the chemical logic of metabolism, and covers the interrelationship of metabolism to life processes of the whole organism. The book lays out a structured approach to the metabolic basis of disease, including discussion of the normal pathways of metabolism, altered pathways leading to disease, and use of molecular genetics in diagnosis and treatment of disease. It also takes a unique comparative approach in which human metabolism is a reference for metabolism in microorganisms and plant design, and presents novel coverage of development and aging, and human health and animal adaptation. The final chapter reviews the past and future promise of new genetic approaches to treatment and bioinformatics. This, the most exhaustive treatment of metabolism currently available, is a useful text for advanced undergraduates and graduates in biochemistry, cell/molecular biology, and biomedicine, as well as biochemistry instructors and investigators in related fields.

Mitochondrial medicine deals with diseases that are related to mitochondrial dysfunction due to a number of causes from free radical damage to genetic mutation. This book is based on extensive data gathered over 30 years of clinical and experimental research. In it, internationally recognized authors share their experience in various fields of their expertise and guide readers through the disease process, from basic biochemical mechanisms to diagnosis to therapeutic aspects.

The book describes molecular principles and mechanisms by which mitochondrial DNA (mtDNA) can drive the occurrence of diseases and the latest understanding of mtDNA biology. The book explores roles of mtDNA mutation and genetic changes in cancer, with a special focus on lung cancer, and the significance of approach, application, and bioethics of mtDNA sequencing. Authors made a great effort to overview roles of mtDNA signaling pathways, base excision repair, methylation, USP30-mediated regulation, mitochondrial ribosome, autophagy pathways, or ROS-dependent signaling in the pathogenesis, diagnosis, prevention and treatment of diseases. It also demonstrates the importance of basic mitochondrial genetics and the relationship between mutations and disease phenotypes and ageing. This book covers not only the basic information of mtDNA, the relationship of mtDNA and disease, but also mtDNA in stem cell and mitochondria and metabolism etc. The book is written for biological and clinical students and researchers in the field of mtDNA–associated diseases.

Genetic testing and genome sequencing have opened up the possibility to clinicians and families to treat diseases, syndromes, and malformations earlier and provide therapeutic interventions.The guest editors seek to provide a basic overview of the topic for the neonatologist/perinatologist. Articles addres dysmorphology, syndromes in the infant, skeletal dysplasias, limb malformations, craniofacial anomolies, GI/liver disease, disorders of sexual develoment, brain defects, inborn errors of metabolism, and congenital heart disease.