Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With 46 subunits, human mitochondrial complex I is the largest enzyme of the oxidative phosphorylation system. We have studied the assembly of complex I in cultured human cells. This will provide essential information about the nature of complex I deficiencies and will enhance our understanding of mitochondrial disease mechanisms. We have found that 143B206 rho zero cells, not containing mitochondrial DNA, are still able to form complex I subcomplexes. To further address the nature of these subcomplexes, we depleted 143B osteosarcoma cells of complex I by inhibiting mitochondrial protein translation with doxycycline. After removing this drug, complex I formation resumes and assembly intermediates were observed by two-dimensional blue native electrophoresis. Analysis of the observed subcomplexes indicates that assembly of human complex I is a semi-sequential process in which different preassembled subcomplexes are joined to form a fully assembled complex. The membrane part of the complex is formed in distinct steps. The B17 subunit is part of a subcomplex to which ND1, ND6 and PSST are subsequently added. This is bound to a hydrophilic subcomplex containing the 30 and 49 kDa subunits, to which a subcomplex including the 39 kDa subunit is incorporated, and later on the 18 and 24 kDa subunits. At a later stage more subunits, including the 15 kDa, are added and holo-complex I is formed. Our results suggest that human complex I assembly resembles that of Neurospora crassa, in which a membrane arm is formed and assembled to a preformed peripheral arm, and support ideas about modular evolution.
Hum Mol Genet 2004 Oct 15
PMID:Human mitochondrial complex I assembles through the combination of evolutionary conserved modules: a framework to interpret complex I deficiencies. 1531 50

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is the most common maternally inherited mitochondrial disease. An A-->G mutation in the transfer RNA(Leu(UUR)) gene at position 3243 of the mitochondrial DNA accounts for most MELAS cases. The transient nature of the stroke-like episodes is reflected in abnormalities on neuroimaging. The cardinal laboratory abnormalities include elevated serum lactate during the acute episodes and respiratory enzyme defects in skeletal muscle. Muscle biopsy also helps confirm the diagnosis by identifying abnormal proliferation of mitochondria. Although current treatment options for MELAS are largely supportive, several therapeutic approaches have been attempted with limited success. Genetic counseling is an important component of patient management in MELAS. Newer reproductive technologies hold promise for reducing the recurrence of MELAS in subsequent generations. Advances in research into gene therapy offer hope of treatment for the future.
Expert Rev Mol Diagn 2004 Sep
PMID:Diagnosis and management of MELAS. 1534 57

Clinical features are reported for 37 patients with various mitochondrial disorders, treated with sodium dichloroacetate (DCA) for 3 weeks to 7 years (mean 3.25 years) at 11-50 mg/kg/day (34.6+/-13.1) in an open-label format. DCA pharmacokinetics showed half-times approximately 86 min for the first intravenous dose of 50 mg/kg, 3.2 h for a subsequent intravenous dose 4-6 h later, and 11 h after continued oral dosing of 12.5-25 mg/kg twice daily. Basal blood and CSF lactate (mean values at entry 29.6 and 46.8 mg/dL, respectively) decreased at 3 months (to 18.1 and 34.2, respectively) and 12 months (to 17.7 and 33.1, respectively). There was some attenuation of the blood lactate response to oral fructose but not glucose, although the baseline lactate was lower with DCA. A standardized neurologic inventory showed stabilization or improvement over one year. The subjective impression of overall disease course was worsening in 21.6%, improvement in 48.6%, and no discernable effect in 29.7%. Among 8 patients who had 17 stroke-like events in 0.25-5 years prior to study entry, there were a total of 2 events over 3-6 years of treatment. In two cases institution of DCA resulted in dramatic relief of severe headaches which had been refractory to narcotics. Given variability of symptoms and limited understanding of natural history of mitochondrial disease, it is difficult to determine the efficacy of DCA in this open-label study, but there did appear to be some cases in which there were at least temporary benefits.
Mol Genet Metab
PMID:Chronic treatment of mitochondrial disease patients with dichloroacetate. 1546 28

Mechanisms of mitochondrial DNA (mtDNA) maintenance have recently gained wide interest owing to their role in inherited diseases as well as in aging. Twinkle is a new mitochondrial 5'-3' DNA helicase, defects of which we have previously shown to underlie a mitochondrial disease, progressive external ophthalmoplegia with multiple mtDNA deletions. Mouse Twinkle is highly similar to the human counterpart, suggesting conserved function. Here, we have characterized the mouse Twinkle gene and expression profile and report that the expression patterns are not conserved between human and mouse, but are synchronized with the adjacent gene MrpL43, suggesting a shared promoter. To elucidate the in vivo role of Twinkle in mtDNA maintenance, we generated two transgenic mouse lines overexpressing wild-type Twinkle. We could demonstrate for the first time that increased expression of Twinkle in muscle and heart increases mtDNA copy number up to 3-fold higher than controls, more than any other factor reported to date. Additionally, we utilized cultured human cells and observed that reduced expression of Twinkle by RNA interference mediated a rapid drop in mtDNA copy number, further supporting the in vivo results. These data demonstrate that Twinkle helicase is essential for mtDNA maintenance, and that it may be a key regulator of mtDNA copy number in mammals.
Hum Mol Genet 2004 Dec 15
PMID:Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA copy number. 1550 89

White matter involvement is recently being realized as a common finding in mitochondrial disorders. It is considered an inherent part of the classical mitochondrial syndromes which are usually associated with alterations in the mitochondrial DNA such as: Leigh disease, Kearns-Sayre syndrome, mitochondrial encephalomyopathy lactic acidosis, and stroke like episodes, mitochondrial neuro-gastro-intestinal encephalomyopathy and Leber's hereditary optic neuropathy. White matter involvement is also described in mitochondrial disorders due to mutations in the nuclear DNA which are transmitted in an autosomal pattern. MRI findings suggestive of a mitochondrial disease are: small cyst-like lesions in abnormal white matter, involvement of both cerebral and cerebellar white matter, and a combination of a leukoencephalopathy with bilateral basal ganglia lesions. The clinical manifestations may be disproportionate to the extent of white matter involvement. Other organs may frequently be involved. The onset is often in infancy with a neurodegenerative course. The finding of a leukoencephalopathy in a patient with a complex neurologic picture and multisystem involvement should prompt a thorough mitochondrial evaluation.
Mol Genet Metab 2005 Feb
PMID:White matter involvement in mitochondrial diseases. 1567 Jul 18

The mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is characterized by the association of gastrointestinal and neurological symptoms. It is a rare autosomal recessive mitochondrial disorder with multiple mitochondrial DNA deletions and/or depletion. It is caused by thymidine phosphorylase (TP) gene mutations resulting in a complete abolition of TP activity. We tested 31 unrelated patients presenting either with a complete MNGIE syndrome (8 patients), a severe intestinal pseudo-obstruction (10 patients), and multiple deletions and/or depletion of mitochondrial DNA (13 patients). All the tested patients presenting with a complete MNGIE had increased thymidine levels in plasma and urine, and no TP activity. The group with pseudo-obstruction syndrome had normal or partial reduction of TP activity. We found pathogenic mutations on TP gene only in the MNGIE syndrome group: all the MNGIE patients were compound heterozygous or homozygous for mutations in the TP gene. Eight of these mutations are yet unreported, confirming the lack of genotype/phenotype correlation in this syndrome. Enzymatic activity and thymidine level are thus rapid diagnosis tests to detect MNGIE affected patients prior to genetic testing for patients with gastrointestinal symptoms.
Mol Genet Metab 2005 Apr
PMID:Thymidine phosphorylase gene mutations in patients with mitochondrial neurogastrointestinal encephalomyopathy syndrome. 1578 Nov 93

A number of human disease-associated sequences have been reported in other species, such as rodents, but compensatory changes appear to prevent these deleterious mutations from being expressed. The aim of this work was to compare the mitochondrial DNA of multiple primates to ascertain whether mitochondrial disease-causing sequences in humans are fixed in nonhuman primates. Indeed, 46 sequences related to human pathology were identified in 1 or more of the 12 studied nonhuman primates, the majority of which were associated with late-onset diseases. Most of these sequences can be explained by the presence of secondary compensatory changes that render these mutations phenotypically inert. Nonetheless, and since humans not only are the longest-lived primate but feature the largest brain, one hypothesis is that a gradual optimization of the human mitochondrion occurred in the hominid lineage driven by the need to optimize the aerobic energy metabolism to delay neurodegeneration. Therefore, it is also proposed that some of these disease-associated sequences in nonhuman primates may be linked to the evolution of human longevity and intelligence, indicating a general pattern of selection on longevity in the course of evolution of the human mitochondrion.
J Mol Evol 2005 Oct
PMID:Human disease-associated mitochondrial mutations fixed in nonhuman primates. 1613 71

Heterogeneous clinical expression of mitochondrial DNA (mtDNA) disorders depends on both qualitative and quantitative changes in mtDNA. We developed a sensitive and effective method that simultaneously detects mtDNA deletion(s) and quantifies total mtDNA content. The percentage of deletions and mtDNA content of 19 patients with single or multiple deletions were analyzed by real-time quantitative polymerase chain reaction (real-time qPCR) using TaqMan probes specific for mtDNA (tRNA leu(UUR), ND4, ATPase8, and D-loop regions) and nuclear DNA (AIB1, beta-2-microglobulin, and beta-actin). The proportion of deletion mutants determined by real-time qPCR was consistent with that determined by Southern analysis. Most patients with mtDNA deletions also demonstrated compensatory mtDNA over-replication. Multiple mtDNA deletions that were not detectable by Southern analysis due to low percentage of each deletion molecule were readily detected and quantified by real-time qPCR. Furthermore, 12 patients with clinical features and abnormal biochemical/histopathological results consistent with mitochondrial respiratory chain disorders without identified mtDNA mutations had either substantially depleted or significantly over-replicated mtDNA content, supporting the diagnosis of mitochondrial disease. Our results demonstrate that both qualitative and quantitative analyses are important in molecular diagnosis of mitochondrial diseases. The presence of deletion(s) and mtDNA depletion or compensatory over-replication can be determined simultaneously by real-time qPCR.
J Mol Diagn 2005 Nov
PMID:Simultaneous detection and quantification of mitochondrial DNA deletion(s), depletion, and over-replication in patients with mitochondrial disease. 1625 60

A number of nuclear mutations have been identified in a variety of mitochondrial diseases including progressive external ophthalmoplegia (PEO), Alpers syndrome and other neuromuscular and oxidative phosphorylation defects. More than 50 mutations have been identified in POLG, which encodes the human mitochondrial DNA (mtDNA) polymerase gamma, PEO and Alpers patients. To rapidly characterize the effects of these mutations, we have developed a versatile system that enables the consequences of homologous mutations, introduced in situ into the yeast mtDNA polymerase gene MIP1, to be evaluated in vivo in haploid and diploid cells. Overall, distinct phenotypes for expression of each of the mip1-PEO mutations were observed, including respiration-defective cells with decreased viability, dominant-negative mutant polymerases, elevated levels of mitochondrial and nuclear DNA damage and chromosomal mutations. Mutations in the polymerase domain caused the most severe phenotype accompanied by loss of mtDNA and cell viability, whereas the mutation in the exonuclease domain showed mild dominance with loss of mtDNA. Interestingly, the linker region mutation caused elevated mitochondrial and nuclear DNA damage. The cellular processes contributing to these observations in the mutant yeast cells are potentially relevant to understanding the pathologies observed in human mitochondrial disease patients.
Hum Mol Genet 2006 Jan 15
PMID:Mitochondrial and nuclear DNA defects in Saccharomyces cerevisiae with mutations in DNA polymerase gamma associated with progressive external ophthalmoplegia. 1636 9

Recently, the human protein responsible for replicative mtDNA helicase activity was identified and designated Twinkle. Twinkle has been implicated in autosomal dominant progressive external ophthalmoplegia (adPEO), a mitochondrial disorder characterized by mtDNA deletions. The Twinkle protein appears to have evolved from an ancestor shared with the bifunctional primase-helicase found in the T-odd bacteriophages. However, the question has been raised as to whether human Twinkle possesses primase activity, due to amino acid sequence divergence and absence of a zinc-finger motif thought to play an integral role in DNA binding. To date, a primase protein participating in mtDNA replication has not been identified in any eukaryote. Here we investigate the wider phylogenetic distribution of Twinkle by surveying and analyzing data from ongoing EST and genome sequencing projects. We identify Twinkle homologues in representatives from five of six major eukaryotic assemblages ("supergroups") and present the sequence of the complete Twinkle gene from two members of Amoebozoa, a supergroup of amoeboid protists at the base of the opisthokont (fungal/metazoan) radiation. Notably, we identify conserved primase motifs including the zinc finger in all Twinkle sequences outside of Metazoa. Accordingly, we propose that Twinkle likely serves as the primase as well as the helicase for mtDNA replication in most eukaryotes whose genome encodes it, with the exception of Metazoa.
J Mol Evol 2006 May
PMID:Twinkle, the mitochondrial replicative DNA helicase, is widespread in the eukaryotic radiation and may also be the mitochondrial DNA primase in most eukaryotes. 1661 44


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