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Mitochondrial function and dysfunction
01 Jan 2002-
TL;DR: This book discusses Mitochondria and Amylotrophic Lateral Sclerosis, as well as models of Mitochondrial Disease, and discusses the role of mitochondria in aging.
Abstract: Mitochondrial Structure and Function: Mitochondrial DNA structure and function. Oxidative phosphorylation structure, function and intermediary metabolism. Import of mitochondrial proteins. Primary Respiratory Chain Disorders: Mitochondrial Disorders of the Nervous System: Clinical, biochemical and molecular genetic features. Secondary Respiratory Chain: Disorders Friedriech's ataxia. Wilson's disease. Hereditary spastic paraplegia. Cytochrome c oxidase deficiency. Toxin Induced Mitochondrial Dysfunction: Toxin Induced Mitochondrial Dysfunction. Neurodegenerative Disorders: Parkinson's disease. Huntington's Disease: The Mystery Unfolds? Alzheimer's disease. Mitochondria and Amylotrophic Lateral Sclerosis. Models of Mitochondrial Disease: Models of Mitochondrial Disease. Apoptosis: Contributions of Mitochondrial Alterations, Resulting from Bad Genes and a Hostile Environment, to the Pathogenesis of Alzheimer's Disease. Defects of ss-Oxidation Including Carnitine Deficiency: Defects of ss-Oxidation Including Carnitine Deficiency. Mitochondrial Involvement in Aging: The Mitochondrial Theory of Aging: Involvement of mtDNA Damage and Repair.
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TL;DR: The results of this study indicate that the local protein synthetic system plays an important role in mitochondrial function and the maintenance of the axon.
Abstract: (1) Axons contain numerous mRNAs and a local protein synthetic system that can be regulated independently of the cell body. (2) In this study, cultured primary sympathetic neurons were employed, to assess the effect of local protein synthesis blockade on axon viability and mitochondrial function. (3) Inhibition of local protein synthesis reduced newly synthesized axonal proteins by 65% and resulted in axon retraction after 6 h. Acute inhibition of local protein synthesis also resulted in a significant decrease in the membrane potential of axonal mitochondria. Likewise, blockade of local protein transport into the mitochondria by transfection of the axons with Hsp90 C-terminal domain decreased the mitochondrial membrane potential by 65%. Moreover, inhibition of the local protein synthetic system also reduced the ability of mitochondria to restore axonal levels of ATP after KCl-induced depolarization. (4) Taken together, these results indicate that the local protein synthetic system plays an important role in mitochondrial function and the maintenance of the axon.
93 citations
TL;DR: Muscle biopsy provides the best tissue to confirm a mitochondrial cytopathy, and quantitative determinations of respiratory chain enzyme complexes, with citrate synthase as an internal control, confirm the histochemical impressions or may be the only evidence of mitochondrial disease.
Abstract: Muscle biopsy provides the best tissue to confirm a mitochondrial cytopathy. Histochemical features often correlate with specific syndromes and facilitate the selection of biochemical and genetic studies. Ragged-red fibres nearly always indicate a combination defect of respiratory complexes I and IV. Increased punctate lipid within myofibers is a regular feature of Kearns-Sayre and PEO, but not of MELAS and MERRF. Total deficiency of succinate dehydrogenase indicates a severe defect in Complex II; total absence of cytochrome-c-oxidase activity in all myofibres correlates with a severe deficiency of Complex IV or of coenzyme-Q10. The selective loss of cytochrome-c-oxidase activity in scattered myofibers, particularly if accompanied by strong succinate dehydrogenase staining in these same fibres, is good evidence of mitochondrial cytopathy and often of a significant mtDNA mutation, though not specific for Complex IV disorders. Glycogen may be excessive in ragged-red zones. Ultrastructure provides morphological evidence of mitochondrial cytopathy, in axons and endothelial cells as well as myocytes. Abnormal axonal mitochondria may contribute to neurogenic atrophy of muscle, a secondary chronic feature. Quantitative determinations of respiratory chain enzyme complexes, with citrate synthase as an internal control, confirm the histochemical impressions or may be the only evidence of mitochondrial disease. Biological and technical artifacts may yield falsely low enzymatic activities. Genetic studies screen common point mutations in mtDNA. The brain exhibits characteristic histopathological alterations in mitochondrial diseases. Skin biopsy is useful for mitochondrial ultrastructure in smooth erector pili muscles and axons; skin fibroblasts may be grown in culture. Mitochondrial alterations occur in many nonmitochondrial diseases and also may be induced by drugs and toxins.
83 citations
TL;DR: Findings establish that proteins requisite for mitochondrial activity are synthesized locally in the axon and nerve terminal, and call attention to the intimacy of the relationship that has evolved between the distant cellular domains of the neuron and its energy generating systems.
Abstract: Axons and presynaptic nerve terminals of both invertebrate and mam- malian SCG neurons contain a heterogeneous population of nuclear-encoded mito- chondrial mRNAs and a local cytosolic protein synthetic system. Nearly one quarter of the total protein synthesized in these structural/functional domains of the neuron is destined for mitochondria. Acute inhibition of axonal protein synthesis markedly reduces the functional activity of mitochondria. The blockade of axonal protein into mitochondria had similar effects on the organelle's functional activity. In addition to mitochondrial mRNAs, SCG axons contain approximately 200 different micro- RNAs (miRs), short, noncoding RNA molecules involved in the posttranscriptional regulation of gene expression. One of these miRs (miR-338) targets cytochrome c oxidase IV (COXIV) mRNA. This nuclear-encoded mRNA codes for a protein that plays a key role in the assembly of the mitochondrial enzyme complex IV and oxidative phosphorylation. Over-expression of miR-338 in the axon markedly decreases COXIV expression, mitochondrial functional activity, and the uptake of neurotransmitter into the axon. Conversely, the inhibition of endogeneous miR-338 levels in the axon significantly increased mitochondrial activity and norepinephrine uptake into the axon. The silencing of COXIV expression in the axon using short, inhibitory RNAs (siRNAs) yielded similar results, a finding that indicated that the effects of miR-338 on mitochondrial activity and axon function were mediated, at least in part, through local COXIV mRNA translation. Taken together, recent findings establish that proteins requisite for mitochondrial activity are synthesized locally in the axon and nerve terminal, and call attention to the intimacy of the relationship that has evolved between the distant cellular domains of the neuron and its energy generating systems.
54 citations
TL;DR: The deletion resulted in significant respiratory chain deficiency in muscle and blood and abnormalities of the platelet mitochondrial membrane potential, and cerebrospinal fluid analysis, magnetic resonance spectroscopy and MRI features suggested inflammatory central nervous system demyelination rather than a primary respiratory chain disorder.
21 citations
TL;DR: The results suggest that p53 plays a key role in the cellular response elicited by OA accumulation in Chang liver cells.
19 citations