Mitochondrial diseases

Human creatine kinase -MM MAK33 IgGl Cardiac disease, mitochondrial disorders, inflammatory myopathies, myasthenia, polymyositis, McArdle s disease, NMJ disorders, muscular dystrophy, ALS, hypo and hyperthyroid disorders, central core disease, acid maltase deficiency, myoglobinuria, rhabdomyolysis, motor neuron diseases, A. thaliana A. thaliana 2S2 seed storage protein SP + 0.02-0.4% TSP of fresh leaf extract (10-12% TSP of intercellular fluid) 52... 

The above data suggest an important role of reactive oxygen species in the development of heart diseases. This suggestion has been supported by many studies, which also demonstrated a potential efficacy of antioxidants, free scavengers, and chelators in the treatment of these diseases. Mitochondrial oxygen radical overproduction can probably be one of the critical causes. 

Chronic meningitis nflammatory bowel disease Mitochondrial disease Fabry s disease Homocystinemia Hypoglycemia/hypercalcemia Fat embolism... 

Fourteen mtDNA tRNA mutations have been associated with maternally inherited disease. Such mutations are typically associated with severe mitochondrial myopathies, characterized by ragged red skeletal muscle fibers upon Gomori trichrome staining and the accumulation of structurally abnormal mitochondria in muscle. Mutations in tRNAs exemplify the threshold effect whereby (due to replicative segragation) individuals may not exhibit clinical signs until the proportion of mutant mtDNA exceeds 80-90%. Myoclonic epilepsy and ragged red fiber (MERRF) disease, mitochondrial encephalomyo-pathy tactic acidosis (MELAS), as well as maternally inherited myopathy and cardiomyopathy (MMC) are well-characterized mitochondrial diseases. 

Cassarino DS, Bennett JP Jr. 1999. An evaluation of the role of mitochondria in neurodegenerative diseases Mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Res Brain Res Rev 29 1-25. 

A mutation in any of the 13 protein subunits, the 22 tRNAs, or the two rRNAs whose genes are carried in mitochondrial DNA may possibly cause disease. The 13 protein subunits are all involved in electron transport or oxidative phosphorylation. The syndromes resulting from mutations in mtDNA frequently affect oxidative phosphorylation (OXPHOS) causing what are often called "OXPHOS diseases." Mitochondrial oxidative phosphorylation also depends upon 100 proteins encoded in the nucleus. Therefore, OXPHOS diseases may result from defects in either mitochondrial or nuclear genes. The former are distinguished by the fact that they are inherited almost exclusively maternally. Most mitochondrial diseases are rare. However, mtDNA is subject to rapid mutation, and it is possible that accumulating mutants in mtDNA may be an important component of aging. " ... 

Ischemia/reperfusion injury following stroke Oxphos diseases (Mitochondrial DNA disorders) Multiple sclerosis Parkinson s disease... 

Parkinson s disease Mitochondrial function defects sensitivity to oxidative stress in LRRK2-mutant neurons [98,99]... 

Pollitt, R. J., 1995. Disorders of mitochondrial long-chain fatty acid oxidation. Journal of Inherited Metabolic Disease 18 473—490. 

Ubiquitous mitochondrial monoamine oxidase [monoamine oxygen oxidoreductase (deaminating) (flavin-containing) EC 1.4.3.4 MAO] exists in two forms, namely type A and type B [ monoamine oxidase (MAO) A and B]. They are responsible for oxidative deamination of primary, secondary, and tertiary amines, including neurotransmitters, adrenaline, noradrenaline, dopamine (DA), and serotonin and vasoactive amines, such as tyramine and phenylethylamine. Their nonselec-tive and selective inhibitors ( selective MAO-A and -B inhibitors) are employed for the treatment of depressive illness and Parkinson s disease (PD). 

Metabolic Myopathies Glycogen Storage Disease Disorders of Lipid Metabolism Respiratory Chain Disorders Mitochondrial DNA Abnormalities Myotonias, Periodic Paralyses, and Malignant Hyperpyrexia Myotonias... 

The inherited diseases of muscle in adults are highly variable. They may be X-linked, autosomal dominant, or autosomal recessive. They may result from germline mosaicism, from a genetically determined predisposition, or from an abnormality in mitochondrial DNA. As a result, these diseases are also variable in age of onset, in the severity of expression of disease, and in the management of the disease. 

The metabolic myopathies are exceptionally complex. Mitochondrial disorders are usually multisystem disorders, in which metabolic dysfunction affects muscle, liver, CNS, and special senses (especially vision) in almost any combination. There is evidence that some forms of mitochondrial disease are inherited, and the preponderance of maternal rather than paternal inheritance is consistent with an abnormality in the mitochondrial genome because almost all (and perhaps all) mitochondria are derived from the ovum. 

Corticosteroids a chronic painless myopathy associated with the long-term use of corticosteroids is a particularly common example of drug-induced muscle disorder. It is almost certain that mild cases are overlooked because steroids are so frequently used to treat inflammatory myopathies such as polymyositis. Fluorinated steroids are particularly frequently implicated, and the incidence of drug-induced muscle disease is dose and time-related. The presence of muscle weakness can even complicate topical steroid therapy. Corticosteroid-induced myopathy is mediated via intramuscular cytosolic steroid receptors. The steroid-receptor complexes inhibit protein synthesis and interfere with oxidative phosphorylation. The myopathy is associated with vacuolar changes in muscle, and the accumulation of cytoplasmic glycogen and mitochondrial aggregations. 

Muratovska a., Lightowlers R. N., Taylor R.W., Turnbull D.M., Smith R.A. J., WiLCE J.A., Martin S.W., Murphy M.P. Targeting peptide nucleic acid (PNA) oligomers to mitochondria within cells by conjugation to lipophilic cations implications for mitochondrial DNA replication, expression and disease. Nucleic Acids Res. 2001 29 1852-1863. 

Adapted from Harding AE Neurological disease and mitochondrial genes.Trends Neurol Sci 1991 14 132. 

Grossman LI (1995) Mitochondrial mutations and human disease. Env Mol Mutag 25 30-37. 

Wallace DC (1992) Mitochondrial genetics a paradigm for aging and degenerative diseases. Science 256 628-632. 

Acute leukemia, acute lymphoma, short-bowel syndrome, liver disease (decreased clearance), diabetes mellitus, mitochondrial disease, and congenital enzyme deficiencies... 

PD affects approximately one million Americans (1% of people over 60 years of age). The average age of onset is 60 years of age, and PD is fairly uncommon in those under age 40. The etiology of PD is unknown, but genetic predisposition, environmental factors, or combinations of these have been proposed to explain why nerve cells in the substantia nigra deteriorate. About 15% of patients with PD have a first-degree relative with the disease. The pathogenesis of cell death (neuron degeneration) may be due to oxidative stress, mitochondrial... 

Biguanides such as metformin are thought to inhibit mitochondrial oxidation of lactic acid, thereby increasing the chance of lactic acidosis occurring. Fortunately, the incidence of lactic acidosis in clinical practice is rare. Patients at greatest risk for developing lactic acidosis include those with liver disease or heavy alcohol use, severe infection, heart failure, and shock. Thus, it is common practice to evaluate liver function prior to initiation of metformin. 

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