The Elusive Magic Pill: Finding Effective Therapies for Mitochondrial Disorders
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The Elusive Magic Pill: Finding Effective Therapies for Mitochondrial Disorders Amy Goldstein & Lynne A. Wolfe
Published online: 25 January 2013 # The American Society for Experimental NeuroTherapeutics, Inc. 2013
Abstract The incidence of mitochondrial diseases has been estimated at 11.5/100,000 (1:8500) worldwide. In the USA up to 4000 newborns annually are expected to develop a mitochondrial disease. More than 50 million adults in the USA also suffer from diseases in which primary or secondary mitochondrial dysfunction is involved. Mitochondrial dysfunction has been identified in cancer, infertility, diabetes, heart diseases, blindness, deafness, kidney disease, liver disease, stroke, migraine, dwarfism, and resulting from numerous medication toxicities. Mitochondrial dysfunction is also involved in normal aging and age-related neurodegenerative diseases, such as Parkinson and Alzheimer diseases. Yet most treatments available are based on empiric data and clinician experience because of the lack of randomized controlled clinical trials to provide evidence-based treatments for these disorders. Here we explore the current state of research for the treatment of mitochondrial disorders. Keywords Mitochondria . ATP . mtDNA . nDNA . Respiratory chain . OXPHOS
Introduction Mitochondria are intracellular organelles found in every human cell that are responsible for generating energy in the form of adenosine triphosphate (ATP). Mitochondria are composed of approximately 1500 proteins, of which approximately 300 are necessary for oxidative phosphorylation and only 13 are A. Goldstein Division of Child Neurology, Childrens Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA L. A. Wolfe (*) Undiagnosed Diseases Program, National Institutes of Health, 10 Center DR, MSC 1205, RM# 3-2551, Bethesda, MD 20892, USA e-mail: [email protected]
encoded by mitochondrial DNA (mtDNA). Most mitochondrial proteins are encoded by the nuclear DNA (nDNA) and must be transcribed, translated, targeted to mitochondria, imported, and then folded and assembled properly in order to carry out normal functions [1, 2]. There are a total of five enzyme complexes in the inner mitochondrial membrane that carry out oxidative phosphorylation (OXPHOS): 1) nicotinamide adenine dinucleotide (NADH)/coenzyme (Co)Q oxidoreductase (complex I); 2) succinate/CoQ oxidoreductase (complex II); 3) cytochrome C reductase (complex III); 4) cytochrome C oxidase (complex IV); and, 5) ATP synthase (complex V). The transfer of electrons moves from complex I and complex II to CoQ to complex III to complex IV releasing oxygen and water. The protons are pumped across the inner mitochondrial membrane generating an electrochemical gradient that allows protons to flow back from the intermembrane space into the mitochondrial matrix through complex V to make ATP [1, 2]. Complex I has approximately 45 polypeptides: 7 encoded from mtDNA and the others encoded by nuclear DNA. Complex II consists of 5 polypeptides, all encoded by nuclear DNA. Complex III is made up of 11 su
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