Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Diabetes mellitus associated with mitochondrial tRNA mutation at position 3243(DM-Mt3243) is a new disease. Patients have a distinctly different picture from MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). During observations at the Saiseikai Central Hospital, the following findings were noted in DM-Mt3243 patients: DM-Mt3243 patients are diagnosed earlier with diabetes, compared to NIDDM (non-insulin dependent diabetes mellitus) controls without family history. DM-Mt3243 patients often need insulin more often than NIDDM controls without family history. Post-treatment neuropathy and insulin edema are often found in DM-Mt3243, and the two phenomena possibly have a similar pathophysiology related to mitochondrial dysfunction. Ambiguous psychiatric disorders of functional psychosis are observed frequently in DM-Mt3243. Mild headache is common in DM-Mt3243 cases. Ambiguous neuromuscular abnormalities such as sleep disturbance, paresthesia of the legs, edema of the legs, and palpitation may be symptoms associated with mitochondrial dysfunction in DM-Mt3243. Coenzyme Q may be effective in the relief of these neuromuscular symptoms.
Mol Aspects Med 1997
PMID:Diabetes mellitus associated with 3243 mitochondrial tRNA(Leu(UUR)) mutation: clinical features and coenzyme Q10 treatment. 926 20

The mitochondrial DNA (mtDNA) codes for essential hydrophobic components of the system of oxidative phosphorylation. Diseases caused by mtDNA defects are manifested as variable clinical phenotypes and the symptoms represent the involvement of tissues with high energy demand. Various approaches have been taken to treat mitochondrial diseases by administration of redox compounds, enzyme activators, vitamins and coenzymes or dietary measures. The MELAS mutation at the base pair 3243 of mitochondrial DNA demolishes a transcription termination sequence located within the tRNA(Leu)[UUR] gene, resulting in synthesis of an abnormally large derivative of 16 S rRNA and defective translation. The activity of NADH:Q oxidoreductase (complex I) is often decreased and lactic acidosis is a typical clinical finding. We hypothesized that defective translation of the seven mitochondrially coded subunits (of the total 41) of complex I may alter its affinity to the NADH substrate in which case the activity decrease may be compensated for by increasing the NADH concentration. A MELAS patient was treated with oral nicotinamide for 5 months. The blood NAD content representing the NAD + NADH pool of erythrocytes rose 24 fold and the blood lactate + pyrovate concentration fell by 50%. All these metabolic alterations suggested an improvement of the function of complex I or the whole mitochondrial respiratory chain. However, the kinetic properties of the patient's complex I were similar to the reference values. A tempting explanation is that the free NADH concentration in mitochondria is normally at the level of K(m), so that the decreased activity of the respiratory chain can be compensated for by increased mitochondrial [NADH]. Another possibility would be that the substrate shuttles for transport of reducing power of cytosolic NADH into mitochondria (the malate aspartate or glycerol-3-phosphate shuttles) may be enhanced by increased total NAD + NADH. Because the malate-aspartate shuttle is actually a pump for reducing equivalents driven by the mitochondrial membrane energization, it is proposed that the exacerbations of the MELAS syndrome be partly due to a vicious circle initiated by a defect of complex I and affecting the active transport of the hydrogen from cytosolic NADH into the mitochondrion.
Mol Cell Biochem 1997 Sep
PMID:Metabolic interventions against complex I deficiency in MELAS syndrome. 930 2

The mouse X-linked mutants lined and stripey are associated with lethality of affected males in utero and a striping of the coat in carrier females. We demonstrate that the underlying mutations are nested deletions which lie in the Phex-Amelx chromosomal segment conserved between man and mouse. The lined deletion contains less than approximately 0.7 cM of genetic material and includes the growth factor-regulated protein kinase gene, Rsk2. Stripey carries a larger deletion which removes approximately 2.0 cM of genetic material, including Rsk2 and the pyruvate dehydrogenase E1alpha subunit gene, Pdha1 . Since Coffin-Lowry syndrome and neonatal lactic acidosis are associated with mutations in the human homologues of Rsk2 and Pdha1 respectively, lined and stripey provide models for gene deficiencies in these disorders.
Hum Mol Genet 1998 Mar
PMID:Mouse mutants carrying deletions that remove the genes mutated in Coffin-Lowry syndrome and lactic acidosis. 946 16

1. The original concept of the ischemic penumbra surrounding a focus of dense cerebral ischemia is based on electrophysiological observations. In the cortex of baboons following middle cerebral artery occlusion, complete failure of the cortical evoked potential was observed at a cerebral blood flow (CBF) threshold level of approx. 0.15 ml/g/min--a level at which extracellular potassium ion activity was only mildly elevated. With a greater CBF decrement to the range of 0.06-0.10 ml/g/min, massive increases in extracellular potassium occurred and were associated with complete tissue infarction. Thus, the ischemic penumbra has been conceptualized as a region in which CBF reduction has exceeded the threshold for failure of electrical function but not that for membrane failure. 2. Recent studies demonstrate that the penumbra as defined classically by the flow thresholds does not survive prolonged periods of ischemia. The correlation of CBF autoradiograms with diffusion-weighted MR images and the regional distribution of cerebral metabolites reveals that the ischemic core region enlarges when adjacent, formerly penumbral, areas undergo irreversible deterioration during the initial hours of vascular occlusion. At the same time, the residual penumbra becomes restricted to the periphery of the ischemic territory, and its fate may depend critically upon early therapeutic intervention. 3. In the border zone of brain infarcts, marked uncoupling of local CBF and glucose utilization is consistently observed. The correlation with electrophysiological measurements shows that metabolism-flow uncoupling is associated with sustained deflections of the direct current (DC) potential resembling transient depolarizations. Such penumbral cell depolarizations, which are associated with an increased metabolic workload, induce episodes of tissue hypoxia due to the constrained collateral flow, stimulate anaerobic glycolysis leading to lactacidosis, suppress protein synthesis, and, finally, compromise energy metabolism. The frequency of their occurrence correlates with the final volume of ischemic injury. Therefore, penumbral depolarizations are regarded as a key event in the pathogenesis of ischemic brain injury. Periinfarct DC deflections can be suppressed by NMDA and non-NMDA antagonists, resulting in a significant reduction of infarct size. 4. The histopathological sequelae within the penumbra consist of various degrees of scattered neuronal injury, also termed "incomplete infarction." The reduction of neuronal density at the infarct border is a flow- and time-dependent event which is accompanied by an early response of glial cells. As early as 3 hr after vascular occlusion a generalized microglial activation can be detected throughout the ipsilateral cortex. Astrocytic activation is observed in the intact parts of the ischemic hemisphere from 6 hr postocclusion onward. Thus, the penumbra is a spatially dynamic brain region of limited viability which is characterized by complex pathophysiological changes involving neuronal function as well as well as glial activation in response to local ischemic injury.
Cell Mol Neurobiol 1998 Dec
PMID:Pathophysiology of the ischemic penumbra--revision of a concept. 987 70

Background: Several mutations in mitochondrial DNA (mtDNA) are associated with the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). The "common" MELAS mutation, A3243G in the tRNA leucine (UUR) gene, affects approximately 80% of cases and is associated with respiratory chain complex I deficiency. Methods and Results: The A3243G mutation creates an ApaI restriction endonuclease site and can be detected by polymerase chain reaction (PCR) amplification of a region of mtDNA containing nt 3243, followed by ApaI digestion and electrophoretic analysis of the resulting fragments. Analysis of mtDNA from a child with complex I deficiency indicated the presence of the mutation homoplasmically in heart, liver, and skeletal muscle. Sequencing revealed only normal tRNA leucine (UUR) sequence, and a novel variant at nt 3426 in the ND1 subunit of complex I, which creates an ApaI site. ApaI digestion results in fragments of similar size to those found in patients with the A3243G mutation. Conclusions: A novel variant at nt 3426 of mtDNA creates an ApaI site and can potentially cause a false-positive result for the presence of the A3243G mutation. Given the highly polymorphic nature of mtDNA, care must be exercised in choosing primers for restriction endonuclease-based diagnostic tests for point mutations, and confirmation of a mutation by an independent method is recommended.
Mol Diagn 1998 Dec
PMID:A False-Positive Diagnosis for the Common MELAS (A3243G) Mutation Caused by a Novel Variant (A3426G) in the ND1 Gene of Mitochondria DNA. 1008 79

We compared responses of turtle heart at 20 degrees C to an anoxic lactic acidosis solution (LA) containing 35 mM lactic acid in an otherwise normal turtle Ringers equilibrated with 3% CO2/97% N2 at pH 7.0) to a solution simulating in vivo anoxic acidosis (VA), with elevated concentrations of lactate, Ca2+, Mg2+, and K+, and decreased Cl-, equilibrated with 10.8% CO2/89.2% N2 at pH 7.0. We examined mechanical properties on cardiac muscle strips and determined intracellular pH (pHi) and high energy phosphates on perfused hearts using 31P-NMR. Maximum active force (Fmax) and the maximum rate of force development (dF/dtmax) of muscle strips were significantly higher during VA than during LA superfusion. An elevation of Ca2+ alone (to 6 mM) in LA significantly increased both Fmax and dF/dtmax but the effects diminished toward the end of the exposure; however, hypercapnic anoxic lactic acidosis (addition of 20 mM HCO3- to LA, equilibrated with 10.8% CO2/89.2% N2, pH 7.0) did not significantly affect Fmax or dF/dtmax. During VA perfusion, pHi (6.73 +/- 0.01) was significantly higher than that during LA perfusion (pHi 6.69 +/- 0.013), but the difference is probably too small to have physiological significance. ATP, creatine phosphate, and inorganic phosphate were not significantly different in the two anoxic solutions. We conclude that the reduction of cardiac mechanical function in vivo is minimized by the integrated effects of changes of ionic concentrations, but the observed changes in Ca2+ and pHi cannot fully explain the effect.
Comp Biochem Physiol A Mol Integr Physiol 1999 Feb
PMID:Different effects of simple anoxic lactic acidosis and simulated in vivo anoxic acidosis on turtle heart. 1032 16

We report a new type of fatal mitochondrial disorder caused by selective deficiency of mitochondrial ATP synthase (ATPase). A hypotrophic newborn from a consanguineous marriage presented severe lactic acidosis, cardiomegaly and hepatomegaly and died from heart failure after 2 days. The activity of oligomycin-sensitive ATPase was only 31-34% of the control, both in muscle and heart, but the activities of cytochrome c oxidase, citrate synthase and pyruvate dehydrogenase were normal. Electrophoretic and western blot analysis revealed selective reduction of ATPase complex but normal levels of the respiratory chain complexes I, III and IV. The same selective deficiency of ATPase was found in cultured skin fibroblasts which showed similar decreases in ATPase content, ATPase hydrolytic activity and level of substrate-dependent ATP synthesis (20-25, 18 and 29-33% of the control, respectively). Pulse-chase labelling of patient fibroblasts revealed low incorporation of [(35)S]methionine into assembled ATPase complexes, but increased incorporation into immunoprecipitated ATPase subunit beta, which had a very short half-life. In contrast, no difference was found in the size and subunit composition of the assembled and newly produced ATPase complex. Transmitochondrial cybrids prepared from enucleated fibroblasts of the patient and rho degrees cells derived from 143B. TK(-)human osteosarcoma cells fully restored the ATPase activity, ATP synthesis and ATPase content, when compared with control cybrids. Likewise, the pattern of [(35)S]methionine labelling of ATPase was found to be normal in patient cybrids. We conclude that the generalized deficiency of mitochondrial ATPase described is of nuclear origin and is caused by altered biosynthesis of the enzyme.
Hum Mol Genet 1999 Oct
PMID:A novel deficiency of mitochondrial ATPase of nuclear origin. 1048 64

Mutations in human mitochondrial tRNA genes are associated with a number of multisystemic disorders. Using an assay that combines tRNA oxidation and circularization we have determined the relative amounts and states of aminoacylation of mutant and wild-type tRNAs in tissue samples from patients with MELAS syndrome (mito- chondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) and MERRF syndrome (myoclonus epilepsy with ragged red fibers), respectively. In most, but not all, biopsies from MELAS patients carrying the A3243G substitution in the mitochondrial tRNA(Leu(UUR))gene, the mutant tRNA is under-represented among processed and/or aminoacylated tRNAs. In contrast, in biopsies from MERRF patients harboring the A8344G substitution in the tRNA(Lys)gene neither the relative abundance nor the aminoacylation of the mutated tRNA is affected. Thus, whereas the A3243G mutation may contribute to the pathogenesis of MELAS by reducing the amount of aminoacylated tRNA(Leu), the A8344G mutation does not affect tRNA(Lys)function in the same way.
Hum Mol Genet 2000 Mar 01
PMID:Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients. 1069 70

Freshwater turtles, and specifically, painted turtles, Chrysemys picta, are the most anoxia-tolerant air-breathing vertebrates. These animals can survive experimental anoxic submergences lasting up to 5 months at 3 degrees C. Two general integrative adaptations underlie this remarkable capacity. First is a profound reduction in energy metabolism to approximately 10% of the normoxic rate at the same temperature. This is a coordinated reduction of both ATP generating mechanisms and ATP consuming pathways of the cells. Second is a defense of acid-base state in response to the extreme lactic acidosis that results from anaerobic glycolysis. Central to this defense is an exploitation of buffer reserves within the skeleton and, in particular, the turtle's shell, its most characteristic structure. Carbonates are released from bone and shell to enhance body fluid buffering of lactic acid and lactic acid moves into shell and bone where it is buffered and stored. The combination of slow metabolic rate and a large and responsive mineral reserve are key to this animal's extraordinary anaerobic capacity.
Comp Biochem Physiol A Mol Integr Physiol 2000 Mar
PMID:Living without oxygen: lessons from the freshwater turtle. 1079 59

We report on a novel frameshift mutation in the mtDNA gene encoding cytochrome c oxidase (COX) subunit III. The proband is an 11-year-old girl with a negative family history and an apparently healthy younger brother. Since 4 years of age, she has developed a progressive spastic paraparesis associated with ophthalmoparesis and moderate mental retardation. The presence of severe lactic acidosis and Leigh-like lesions of putamina prompted us to perform muscle and skin biopsies. In both, a profound, isolated defect of COX was found by histochemical and biochemical assays. Sequence analysis of muscle mtDNA resulted in the identification of a virtually homoplasmic frameshift mutation in the COIII gene, due to the insertion of an extra C at nucleotide position 9537 of mtDNA. Although the 9537C(ins) does not impair transcription of COIII, no full-length COX III protein was detected in mtDNA translation assays in vivo. Western blot analysis of two-dimensional blue-native electrophoresis showed a reduction of specific crossreacting material and the accumulation of early-assembly intermediates of COX, whereas the fully assembled complex was absent. One of these intermediates had an electrophoretic mobility different from those seen in controls, suggesting the presence of a qualitative abnormality of COX assembly. Immunostaining with specific antibodies failed to detect the presence of several smaller subunits in the complex lacking COX III, in spite of the demonstration that these subunits were present in the crude mitochondrial fraction of patient's cultured fibroblasts. Taken together, the data indicate a role for COX III in the incorporation and maintenance of smaller COX subunits within the complex.
Hum Mol Genet 2000 Nov 01
PMID:A novel frameshift mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome c oxidase in a patient affected by Leigh-like syndrome. 1106 32


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