Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.3.5.1 (succinate dehydrogenase)
8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene transfer from the mitochondrion to the nucleus, a process of outstanding importance to the evolution of the eukaryotic cell, is an on-going phenomenon in higher plants. After transfer, the mitochondrial gene has to be adapted to the nuclear context by acquiring a new promoter and targeting information to direct the protein back to the organelle. To better understand the strategies developed by higher plants to transfer organellar genes during evolution, we investigated the fate of the mitochondrial RPL5-RPS14 locus in grasses. While maize mitochondrial genome does not contain RPS14 and RPL5 genes, wheat mitochondrial DNA contains an intact RPL5 gene and a nonfunctional RPS14 pseudogene. RPL5 and PsiRPS14 are co-transcribed and their transcripts are edited. In wheat, the functional RPS14 gene is located in the nucleus, within the intron of the respiratory complex II iron-sulfur subunit gene (SDH2). Its organization and expression mechanisms are similar to those previously described in maize and rice, allowing us to conclude that RPS14 transfer and nuclear activation occurred before divergence of these grasses. Unexpectedly, we found evidence for a more recent RPL5 transfer to the nucleus in wheat. This nuclear wheat RPL5 acquired its targeting information by duplication of an existing targeting presequence for another mitochondrial protein, ribosomal protein L4. Thus, mitochondrial and nuclear functional RPL5 genes appear to be maintained in wheat, supporting the hypothesis that in an intermediate stage of the transfer process, both nuclear and mitochondrial functional genes coexist. Finally, we show that RPL5 has been independently transferred to the nucleus in the maize lineage and has acquired regulatory elements for its expression and a mitochondrial targeting peptide from an unknown source.
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PMID:Transfer of RPS14 and RPL5 from the mitochondrion to the nucleus in grasses. 1469 79

Hepatic oncocytes with abundant granular, eosinophilic cytoplasm due to mitochondrial hyperplasia are seen in various chronic liver diseases, particularly chronic hepatitis and cirrhosis. Increased mitochondria in oncocytes are thought to be a compensatory mechanism for deficiencies in the hepatocellular respiratory chain, although the pathogenesis of these deficiencies has been uncertain. We selected seven cases of cirrhosis (six with oncocytes, one without) for the following analysis: histoenzymatic and immunohistochemical staining of several mitochondrial DNA (mtDNA)- and nuclear DNA (nDNA)-encoded respiratory chain enzymes; immunostaining using antibodies against double-strand-DNA (anti-DNA) and against Ki-67 (a cell proliferation marker); and Southern blot analysis for mtDNA and nDNA. Eighty percent of oncocytes showed histoenzymatic and immunohistochemical deficiencies of cytochrome c oxidase and the mtDNA-encoded subunit I of complex IV, with preserved expression of nDNA-encoded succinate dehydrogenase and the iron-sulfur subunit of complex III (FeS). Cytoplasmic (but not nuclear) anti-DNA staining was partially or completely absent in approximately 50% of oncocytes. Three cases with oncocytes studied by Southern blot showed mtDNA reductions of 66%, 71%, and 85%. In conclusion, hepatic oncocytes demonstrate significant deficiencies of mtDNA and mtDNA-encoded respiratory chain enzymes. We propose that mtDNA depletion plays an important role in hepatocellular oncocytic transformation.
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PMID:Mitochondrial DNA dysfunction in oncocytic hepatocytes. 1470 2

Germline mutations in succinate dehydrogenase subunits B, C and D (SDHB, SDHC and SDHD), genes encoding subunits of mitochondrial complex II, cause hereditary paragangliomas and phaeochromocytomas. In SDHB (1p36)- and SDHC (1q21)-linked families, disease inheritance is autosomal dominant. In SDHD (11q23)-linked families, the disease phenotype is expressed only upon paternal transmission of the mutation, consistent with maternal imprinting. However, SDHD shows biallelic expression in brain, kidney and lymphoid tissues (Baysal et al., 2000). Moreover, consistent loss of the wild-type (wt) maternal allele in SDHD-linked tumours suggests expression of the maternal SDHD allele in normal paraganglia. Here we demonstrate exclusive loss of the entire maternal chromosome 11 in SDHD-linked paragangliomas and phaeochromocytomas, suggesting that combined loss of the wt SDHD allele and maternal 11p region is essential for tumorigenesis. We hypothesize that this is driven by selective loss of one or more imprinted genes in the 11p15 region. In paternally, but not in maternally derived SDHD mutation carriers, this can be achieved by a single event, that is, non-disjunctional loss of the maternal chromosome 11. Thus, the exclusive paternal transmission of the disease can be explained by a somatic genetic mechanism targeting both the SDHD gene on 11q23 and a paternally imprinted gene on 11p15.5, rather than imprinting of SDHD.
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PMID:Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families. 1506 8

When cells are deprived of iron, their growth is invariably inhibited. However, the mechanism involved remains largely unclear. Recently, we have reported that subcytotoxic concentration of deferoxamine mesylate (DFO), an iron chelator, specifically inhibited transition of Chang cell, a normal hepatocyte cell line, from G1 to S phase, which was accompanied by irreversible appearance of senescent biomarkers. To investigate factors responsible for the irreversible arrest, we examined mitochondrial activities because they require several irons for their proper structure and function. After exposure to 1 M DFO, total cellular ATP level was irreversibly decreased with concurrent disruption of mitochondrial membrane potential (DeltaPsim), implying that it might be one of the crucial factors involved in the arrest. DFO did not directly inhibit the mitochondrial respiratory activities in vitro. Among the respiratory activities, complex II activity was specifically inhibited through a down-regulation of the expression of its iron-sulfur subunit. We also observed that mitochondrial morphology was drastically changed to highly elongated form. Our results suggest that mitochondrial function is sensitive to cellular iron level and iron deprivation might be involved in inducing the senescent arrest. In addition, complex II, which is a part of both oxidative phosphorylation and the Krebs cycle, could be one of the critical factors that regulate mitochondrial function by responding to iron levels.
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PMID:Mitochondrial dysfunction via disruption of complex II activity during iron chelation-induced senescence-like growth arrest of Chang cells. 1512 90

We have isolated a Kluyveromyces lactis mutant unable to grow on all respiratory carbon sources with the exception of lactate. Functional complementation of this mutant led to the isolation of KlSDH1, the gene encoding the flavoprotein subunit of the succinate dehydrogenase (SDH) complex, which is essential for the aerobic utilization of carbon sources. Despite the high sequence conservation of the SDH genes in Saccharomyces cerevisiae and K. lactis, they do not have the same relevance in the metabolism of the two yeasts. In fact, unlike SDH1, KlSDH1 was highly expressed under both fermentative and nonfermentative conditions. In addition to this, but in contrast with S. cerevisiae, K. lactis strains lacking KlSDH1 were still able to grow in the presence of lactate. In these mutants, oxygen consumption was one-eighth that of the wild type in the presence of lactate and was normal with glucose and ethanol, indicating that the respiratory chain was fully functional. Northern analysis suggested that alternative pathway(s), which involves pyruvate decarboxylase and the glyoxylate cycle, could overcome the absence of SDH and allow (i) lactate utilization and (ii) the accumulation of succinate instead of ethanol during growth on glucose.
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PMID:The deletion of the succinate dehydrogenase gene KlSDH1 in Kluyveromyces lactis does not lead to respiratory deficiency. 1518 81

Hereditary paraganglioma (PGL) is characterized by the development of slow-growing and vascularized tumors in the paraganglionic system. PGL is caused by germ line heterozygous inactivating mutations in the SDHB (PGL4), SDHC (PGL3), or SDHD (PGL1) genes, which encode three of the four subunits of mitochondrial complex II (succinate dehydrogenase; SDH). Common tumor sites include the carotid body in the neck and paraganglia in the abdomen. The risk of tumor development associated with SDHD mutations is determined by the sex of the transmitting parent, because only a paternal transmission leads to tumorigenesis in the progeny. This transmission pattern suggests operation of genomic imprinting on the SDHD gene. There is also evidence that the risk of tumor development increases at higher altitudes among SDHD mutation carriers. Accordingly, the increased prevalence of SDHD mutations in the Netherlands, attributable to multiple founder mutations, has been explained in part by the low altitudes in this country, which presumably reduce gene penetrance and relax the natural selection. Thus, PGL caused by SDHD mutations represents an unusual example of an inherited monogenic tumor syndrome because the risk of tumorigenesis shows an absolute dependence on the sex of the transmitting parent and may be modified by a ubiquitous environmental factor.
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PMID:Genomic imprinting and environment in hereditary paraganglioma. 1526 76

The nuclear-encoded protein RPS14 (ribosomal protein S14) of rice mitochondria is synthesized in the cytosol as a polyprotein consisting of a large N-terminal domain comprising preSDHB (succinate dehydrogenase B precursor) and the C-terminal RPS14. After the preSDHB-RPS14 polyprotein is transported into the mitochondrial matrix, the protein is processed into three peptides: the N-terminal prepeptide, the SDHB domain and the C-terminal mature RPS14. Here we report that the general MPP (mitochondrial processing peptidase) plays an essential role in processing of the polyprotein. Purified yeast MPP cleaved both the N-terminal presequence and the connector region between SDHB and RPS14. Moreover, the connector region was processed more rapidly than the presequence. When the site of cleavage between SDHB and RPS14 was determined, it was located in an MPP processing motif that has also been shown to be present in the N-terminal presequence. Mutational analyses around the cleavage site in the connector region suggested that MPP interacts with multiple sites in the region, possibly in a similar manner to the interaction with the N-terminal presequence. In addition, MPP preferentially recognized the unfolded structure of preSDHB-RPS14. In mitochondria, MPP may recognize the stretched polyprotein during passage of the precursor through the translocational apparatus in the inner membrane, and cleave the connecting region between the SDHB and RPS14 domains even before processing of the presequence.
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PMID:Recognition and processing of a nuclear-encoded polyprotein precursor by mitochondrial processing peptidase. 1545 88

Mutations within three genes, SDHB, SDHC, and SDHD, encoding distinct subunits of a hetero-oligomeric protein known as the mitochondrial complex II, a component of the mitochondrial electron transport chain and the Krebs cycle have been implicated in the pathogenesis of hereditary paraganglioma (PGL). This study describes a mutation screen of SDHB, SDHC, and SDHD in blood and tumor samples of 14 sporadic and three familial cases of head and neck PGL (HNP). Germline mutations in SDHB and SDHD were identified in two of the three affected individuals with familial HNP. The SDHB mutation was a novel 3 base pair, in-frame deletion of AGC at nucleotide 583-585 encoding serine (delS195). The SDHD mutation was a C to T transition within codon 81 causing substitution of proline with leucine (P81L). In contrast to familial cases, no germline or somatic mutations were identified in the 14 sporadic cases of HNP. The presence of mutations within SDHB and SDHD in two of the three samples of familial PGLs and absence of mutations in sporadic cases is consistent with the significant contribution of these genes to familial but not sporadic PGL. The etiology of sporadic PGL remains to be elucidated.
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PMID:SDHB, SDHC, and SDHD mutation screen in sporadic and familial head and neck paragangliomas. 1547 92

Germline mutations in the succinate dehydrogenase (SDH) (mitochondrial respiratory chain complex II) subunit B gene, SDHB, cause susceptibility to head and neck paraganglioma and phaeochromocytoma. Previously, we did not identify somatic SDHB mutations in sporadic phaeochromocytoma, but SDHB maps to 1p36, a region of frequent loss of heterozygosity (LOH) in neuroblastoma as well. Hence, to evaluate SDHB as a candidate neuroblastoma tumour suppressor gene (TSG) we performed mutation analysis in 46 primary neuroblastomas by direct sequencing, but did not identify germline or somatic SDHB mutations. As TSGs such as RASSF1A are frequently inactivated by promoter region hypermethylation, we designed a methylation-sensitive PCR-based assay to detect SDHB promoter region methylation. In 21% of primary neuroblastomas and 32% of phaeochromocytomas (32%) methylated (and unmethylated) alleles were detected. Although promoter region methylation was also detected in two neuroblastoma cell lines, this was not associated with silencing of SDHB expression, and treatment with a demethylating agent (5-azacytidine) did not increase SDH activity. These findings suggest that although germline SDHB mutations are an important cause of phaeochromocytoma susceptibility, somatic inactivation of SDHB does not have a major role in sporadic neural crest tumours and SDHB is not the target of 1p36 allele loss in neuroblastoma and phaeochromocytoma.
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PMID:Investigation of the role of SDHB inactivation in sporadic phaeochromocytoma and neuroblastoma. 1550 28

Three different nuclear genes encode the essential iron-sulfur subunit of mitochondrial complex II (succinate dehydrogenase) in Arabidopsis (Arabidopsis thaliana), raising interesting questions about their origin and function. To find clues about their role, we have undertaken a detailed analysis of their expression. Two genes (SDH2-1 and SDH2-2) that likely arose via a relatively recent duplication event are expressed in all organs from adult plants, whereas transcripts from the third gene (SDH2-3) were not detected. The tissue- and cell-specific expression of SDH2-1 and SDH2-2 was investigated by in situ hybridization. In flowers, both genes are regulated in a similar way. Enhanced expression was observed in floral meristems and sex organ primordia at early stages of development. As flowers develop, SDH2-1 and SDH2-2 transcripts accumulate in anthers, particularly in the tapetum, pollen mother cells, and microspores, in agreement with an essential role of mitochondria during anther development. Interestingly, in contrast to the situation in flowers, only SDH2-2 appears to be expressed at a significant level in root tips. Strong labeling was observed in all cell layers of the root meristematic zone, and a cell-specific pattern of expression was found with increasing distance from the root tip, as cells attain their differentiated state. Analysis of transgenic Arabidopsis plants carrying SDH2-1 and SDH2-2 promoters fused to the beta-glucuronidase reporter gene indicate that both promoters have similar activities in flowers, driving enhanced expression in anthers and/or pollen, and that only the SDH2-2 promoter is active in root tips. These beta-glucuronidase staining patterns parallel those obtained by in situ hybridization, suggesting transcriptional regulation of these genes. Progressive deletions of the promoters identified regions important for SDH2-1 expression in anthers and/or pollen and for SDH2-2 expression in anthers and/or pollen and root tips. Interestingly, regions driving enhanced expression in anthers are differently located in the two promoters.
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PMID:Nuclear SDH2-1 and SDH2-2 genes, encoding the iron-sulfur subunit of mitochondrial complex II in Arabidopsis, have distinct cell-specific expression patterns and promoter activities. 1556 21


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