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Author: Gregory Randall Wagner Publisher: ISBN: Category : Acetylation Languages : en Pages : 252
Book Description
Friedreich's Ataxia (FRDA) is a rare and poorly understood autosomal recessive disease caused by a pathological deficiency of the mitochondrial protein frataxin. Patients suffer neurodegeneration, ataxia, diabetes, and heart failure. In an effort to understand the mechanisms of heart failure in FRDA, we investigated the role of the protein modification acetylation, which is highly abundant on mitochondrial proteins and has been implicated in regulating intermediary metabolism. Using mouse models of FRDA, we found that cardiac frataxin deficiency causes progressive hyperacetylation of mitochondrial proteins which is correlated with loss of respiratory chain subunits and an altered mitochondrial redox state. Mitochondrial protein hyperacetylation could be reversed by the mitochondria-localized deacetylase SIRT3 in vitro, suggesting a defect in endogenous SIRT3 activity. Consistently, frataxin-deficient cardiac mitochondria showed significantly decreased rates of fatty acid oxidation and complete oxidation to carbon dioxide. However, the degree of protein hyperacetylation in FRDA could not be fully explained by SIRT3 loss. Our data suggested that intermediary metabolites and perhaps acetyl-CoA, which is required for protein acetylation, are accumulating in frataxin-deficient mitochondria. Upon testing the hypothesis that mitochondrial protein acetylation is non-enzymatic, we found that the minimal chemical conditions of the mitochondrial matrix are sufficient to cause widespread non-enzymatic protein acetylation in vitro. These data suggest that mitochondrial protein hyperacetylation in FRDA cardiomyopathy mediates progressive post-translational suppression of mitochondrial oxidative pathways which is caused by a combination of SIRT3 deficiency and, likely, an accumulation of unoxidized acetyl-CoA capable of initiating non-enzymatic protein acetylation. These findings provide novel insight into the mechanisms underlying a poorly understood and fatal cardiomyopathy and highlight a fundamental biochemical mechanism that had been previously overlooked in biological systems.
Author: Gregory Randall Wagner Publisher: ISBN: Category : Acetylation Languages : en Pages : 252
Book Description
Friedreich's Ataxia (FRDA) is a rare and poorly understood autosomal recessive disease caused by a pathological deficiency of the mitochondrial protein frataxin. Patients suffer neurodegeneration, ataxia, diabetes, and heart failure. In an effort to understand the mechanisms of heart failure in FRDA, we investigated the role of the protein modification acetylation, which is highly abundant on mitochondrial proteins and has been implicated in regulating intermediary metabolism. Using mouse models of FRDA, we found that cardiac frataxin deficiency causes progressive hyperacetylation of mitochondrial proteins which is correlated with loss of respiratory chain subunits and an altered mitochondrial redox state. Mitochondrial protein hyperacetylation could be reversed by the mitochondria-localized deacetylase SIRT3 in vitro, suggesting a defect in endogenous SIRT3 activity. Consistently, frataxin-deficient cardiac mitochondria showed significantly decreased rates of fatty acid oxidation and complete oxidation to carbon dioxide. However, the degree of protein hyperacetylation in FRDA could not be fully explained by SIRT3 loss. Our data suggested that intermediary metabolites and perhaps acetyl-CoA, which is required for protein acetylation, are accumulating in frataxin-deficient mitochondria. Upon testing the hypothesis that mitochondrial protein acetylation is non-enzymatic, we found that the minimal chemical conditions of the mitochondrial matrix are sufficient to cause widespread non-enzymatic protein acetylation in vitro. These data suggest that mitochondrial protein hyperacetylation in FRDA cardiomyopathy mediates progressive post-translational suppression of mitochondrial oxidative pathways which is caused by a combination of SIRT3 deficiency and, likely, an accumulation of unoxidized acetyl-CoA capable of initiating non-enzymatic protein acetylation. These findings provide novel insight into the mechanisms underlying a poorly understood and fatal cardiomyopathy and highlight a fundamental biochemical mechanism that had been previously overlooked in biological systems.
Author: Amanda R. Stram Publisher: ISBN: Category : Languages : en Pages : 150
Book Description
Rationale: The childhood heart disease of Friedreich's Ataxia (FRDA) is characterized by hypertrophy and failure. It is caused by loss of frataxin (FXN), a mitochondrial protein involved in energy homeostasis. FRDA model hearts have increased mitochondrial protein acetylation and impaired sirtuin 3 (SIRT3) deacetylase activity. Protein acetylation is an important regulator of cardiac metabolism and SIRT3 is protective in heart disease. The underlying pathophysiology of heart failure in FRDA is unclear. I suspect that increased acetylation in FRDA heart mitochondria damages cardiac energy homeostasis by inhibiting activity of key enzymes involved in heart metabolism. Objective: My project tested the hypothesis that altered acetylation of mitochondrial proteins contributes to the cardiomyopathy of FRDA. Methods: Conditional mouse models of FRDA cardiomyopathy with ablation of FXN (FXN KO) or FXN and SIRT3 (FXN/SIRT3 DKO) in the heart were compared to healthy controls. Hearts were evaluated using echocardiography, cardiac catheterization, histology, protein acetylation and expression. FXN KO mice were treated with NAD+ replacement therapy with nicotinamide riboside (NR), and FXN/SIRT3 DKO mice were treated with FXN protein replacement therapy. Results: Acetylation was temporally progressive and paralleled evolution of heart failure in the FXN KO model. High levels of acetylation were associated with cardiac fibrosis, mitochondrial damage, impaired fat metabolism, and diastolic and systolic dysfunction. Acetylation correlated strongly with worse heart function, and loss of SIRT3 in the FXN KO mouse resulted in significant decrease in ejection fraction and fractional shortening. Treatment of the FXN/SIRT3 DKO with FXN protein therapy reduced acetylation but was not sufficient to fully rescue heart function. Increasing NAD+ with NR-treatment in the FXN KO lead to increased mitochondrial protein acetylation and did not improve cardiac outcome. Conclusion: I found a strong negative correlation between heart function and mitochondrial protein acetylation. My findings also provide evidence that absence of SIRT3 expression in the FXN KO heart exacerbates features of heart failure, and that SIRT3 expression is necessary to rescue the FXN KO heart. These results suggest that SIRT3 inactivation and abnormal acetylation contribute to the pathophysiology of heart disease in FRDA.
Author: Lawrence H. Lash Publisher: Elsevier ISBN: 1483218619 Category : Science Languages : en Pages : 527
Book Description
Methods in Toxicology, Volume 2: Mitochondrial Dysfunction provides a source of methods, techniques, and experimental approaches for studying the role of abnormal mitochondrial function in cell injury. The book discusses the methods for the preparation and basic functional assessment of mitochondria from liver, kidney, muscle, and brain; the methods for assessing mitochondrial dysfunction in vivo and in intact organs; and the structural aspects of mitochondrial dysfunction are addressed. The text also describes chemical detoxification and metabolism as well as specific metabolic reactions that are especially important targets or indicators of damage. The methods for measurement of alterations in fatty acid and phospholipid metabolism and for the analysis and manipulation of oxidative injury and antioxidant systems are also considered. The book further tackles additional methods on mitochondrial energetics and transport processes; approaches for assessing impaired function of mitochondria; and genetic and developmental aspects of mitochondrial disease and toxicology. The text also looks into mitochondrial DNA synthesis, covalent binding to mitochondrial DNA, DNA repair, and mitochondrial dysfunction in the context of developing individuals and cellular differentiation. Microbiologists, toxicologists, biochemists, and molecular pharmacologists will find the book invaluable.
Author: Anthony R. White Publisher: Academic Press ISBN: 0128045639 Category : Medical Languages : en Pages : 468
Book Description
Biometals in Neurodegenerative Diseases: Mechanisms and Therapeutics is an authoritative and timely resource bringing together the major findings in the field for ease of access to those working in the field or with an interest in metals and their role in brain function, disease, and as therapeutic targets. Chapters cover metals in Alzheimer’s Disease, Parkinson’s Disease, Motor Neuron Disease, Autism and lysosomal storage disorders. This book is written for academic researchers, clinicians and advanced graduate students studying or treating patients in neurodegeneration, neurochemistry, neurology and neurotoxicology. The scientific literature in this field is advancing rapidly, with approximately 300 publications per year adding to our knowledge of how biometals contribute to neurodegenerative diseases. Despite this rapid increase in our understanding of biometals in brain disease, the fields of biomedicine and neuroscience have often overlooked this information. The need to bring the research on biometals in neurodegeneration to the forefront of biomedical research is essential in order to understand neurodegenerative disease processes and develop effective therapeutics. Authoritative and timely resource bringing together the major findings in the field for those with an interest in metals and their role in the brain function, disease, and as therapeutic targets Written for academic researchers, clinicians, and advanced graduate students studying, or treating, patients in neurodegeneration, neurochemistry, neurology and neurotoxicology Edited by international leaders in the field who have contributed greatly to the study of metals in neurodegenerative diseases
Author: John McMurry Publisher: Roberts and Company Publishers ISBN: 9780974707716 Category : Medical Languages : en Pages : 524
Book Description
Intended for advanced undergraduates and graduate students in all areas of biochemistry, The Organic Chemistry of Biological Pathways provides an accurate treatment of the major biochemical pathways from the perspective of mechanistic organic chemistry.
Author: Rita Sattler Publisher: Springer ISBN: 331989689X Category : Medical Languages : en Pages : 321
Book Description
It has become evident over the last years that abnormalities in RNA processing play a fundamental part in the pathogenesis of neurodegenerative diseases. Cellular viability depends on proper regulation of RNA metabolism and subsequent protein synthesis, which requires the interplay of many processes including transcription, pre--‐mRNA splicing, mRNA editing as well as mRNA stability, transport and translation. Dysfunction in any of these processes, often caused by mutations in the coding and non--‐ coding RNAs, can be very destructive to the cellular environment and consequently impair neural viability. The result of this RNA toxicity can lead to a toxic gain of function or a loss of function, depending on the nature of the mutation. For example, in repeat expansion disorders, such as the newly discovered hexanucleotide repeat expansion in theC9orf72 gene found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a toxic gain of function leads to the formation of RNA foci and the sequestration of RNA binding proteins (RBPs). This in return leads to a loss of function of those RBPs, which is hypothesized to play a significant part in the disease progression of ALS and FTD. Other toxicities arising from repeat expansions are the formation of RNA foci, bi--‐directional transcription and production of repeat associated non--‐ATG (RAN) translation products. This book will touch upon most of these disease mechanisms triggered by aberrant RNA metabolism and will therefore provide a broad perspective of the role of RNA processing and its dysfunction in a variety of neurodegenerative disorders, including ALS, FTD, Alzheimer’s disease, Huntington’s disease, spinal muscular atrophy, myotonic dystrophy and ataxias. The proposed authors are leading scientists in the field and are expected to not only discuss their own work, but to be inclusive of historic as well as late breaking discoveries. The compiled chapters will therefore provide a unique collection of novel studies and hypotheses aimed to describe the consequences of altered RNA processing events and its newest molecular players and pathways.
Author: Frederick J. Suchy Publisher: Cambridge University Press ISBN: 1108911374 Category : Medical Languages : en Pages : 875
Book Description
Liver disease in children is increasing in prevalence, placing a huge burden on healthcare systems and often requiring long-term management. Offering an integrative approach to the science and clinical practice of pediatric hepatology, this is the definitive reference text for improved diagnosis and treatment strategies. In the new edition of this authoritative text, chapters have been thoroughly revised in line with major advances in the field, such as recognizing the increased frequency of fatty liver disease, and how genetic testing has the potential to establish earlier diagnoses for a variety of diseases. Disorders covered include cholestasis, metabolic disorders and hepatitis, with their presentation across the spectrum of infancy, childhood and adolescence discussed. The indications and surgical aspects of liver transplant are explained and post-transplant care is described in detail. This is a valuable resource for pediatricians, hepatologists, gastroenterologists and all clinicians involved in the care of children with liver diseases.
Author: Mario Ubaldo Manto Publisher: Cambridge University Press ISBN: 1139487264 Category : Medical Languages : en Pages : 313
Book Description
During the last three decades, many laboratories worldwide have dedicated their research activities to understanding the roles of the cerebellum in motor control, cognitive processes and the biology of mental processes, behavioral symptoms and emotion. These advances have been associated with discoveries of new clinical disorders, in particular in the field of genetic ataxias, and the growing number of diseases presents a source of difficulty for clinicians during daily practice. This practical guide summarizes and evaluates current knowledge in the field of cerebellar disorders. Encompassing details of both common and uncommon cerebellar ataxias, including vascular, immune, neoplastic, infectious, traumatic, toxic and inherited disorders, this book will assist clinicians in the diagnosis and management of the full spectrum of cerebellar ataxias encountered in daily practice. Essential reading for clinicians, including general practitioners, neurologists, pediatricians, radiologists, psychiatrists and neuropsychologists, this will also prove a valuable tool for students, trainees and researchers.
Author: Jacob Peedicayil Publisher: Elsevier ISBN: 0443185174 Category : Science Languages : en Pages : 418
Book Description
Neuropsychiatric Disorders and Epigenetics, Second Edition is a comprehensive reference on the epigenetic basis of common neuropsychiatric disorders. The volume is organized into chapters covering individual neuropsychiatric disorders, from addiction to anxiety and autism spectrum disorders, and is contributed by leading experts in their respective fields. The epigenetic aspects of each disorder are discussed, in the context of the full range of associated epigenetic mechanisms, including DNA modification, histone post-translational modification, chromatin organization, and non-coding RNA. A particular emphasis is placed on potential epigenetic interventions, when the effects of environmental stimuli on epigenetic states is particularly relevant to disease. This new edition has been fully updated to reflect recent research advances enabled by genomic technologies, as well as therapeutic interventions for previously unmanageable disorders. Several new chapters have been added on disorders or approaches not considered in the earlier edition, including epigenetics and anxiety disorders, epigenetics and neuroimaging in neuropsychiatric disorders, genome-wide approaches to epigenetic research, and the epigenetics of spinal muscular atrophy. By helping to define epigenetics as a key player in neuropsychiatric disorders, this volume empowers new research, clinical translation, and pharmacological advances, and highlights promising directions for ongoing investigation. Analyzes the effects of environmental stimuli on epigenetic states that correlate with neuropsychiatric disease induction Reviews the epigenetic basis for common neuropsychiatric disorders, thereby guiding translational therapies for clinicians and mechanistic studies for scientists Features extensive use of diagrams, illustrations, tables, and graphical abstracts for each section to reinforce understanding Includes chapter contributions from leading global experts
Author: Gregory Randall Wagner
Author: Gregory Randall Wagner
Author: Amanda R. Stram
Author: Lawrence H. Lash
Author: Anthony R. White
Author: Juan M. Pascual
Author: John McMurry
Author: Rita Sattler
Author: Frederick J. Suchy
Author: Mario Ubaldo Manto
Author: Jacob Peedicayil