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Results for “mitochondrial gene expression”

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PubMed2006

Defective mitochondrial gene expression results in reactive oxygen species-mediated inhibition of respiration and reduction of yeast life span.

Mitochondrial dysfunction causes numerous human diseases and is widely believed to be involved in aging. However, mechanisms through which compromised mitochondrial gene expression elicits the reported variety of cellular defects remain unclear. The amino-terminal domain (ATD) of yeast mitochondrial RNA polymerase is required to couple transcription to translation during expression of mitochondrial DNA-encoded oxidative phosphorylation subunits. Here we report that several ATD mutants exhibit reduced chronological life span. The most severe of these (harboring the rpo41-R129D mutation) displays imbalanced mitochondrial translation, conditional inactivation of respiration, elevated production of reactive oxygen species (ROS), and increased oxidative stress. Reduction of ROS, via overexpression of superoxide dismutase (SOD1 or SOD2 product), not only greatly extends the life span of this mutant but also increases its ability to respire. Another ATD mutant with similarly reduced respiration (rpo41-D152A/D154A) accumulates only intermediate levels of ROS and has a less severe life span defect that is not rescued by SOD. Altogether, our results provide compelling evidence for the "vicious cycle" of mitochondrial ROS production and lead us to propose that the amount of ROS generated depends on the precise nature of the mitochondrial gene expression defect and initiates a downward spiral of oxidative stress only if a critical threshold is crossed.

DNA-Binding Proteins↗

PubMed2005

Increased mitochondrial gene expression during L6 cell myogenesis is accelerated by insulin.

Insulin is the most potent anabolic hormone. The greatest sensitivity to insulin is exhibited by muscle, liver and adipose cells. To study links between insulin and mitochondrial function over the course of cellular quiescence and differentiation, we quantified mitochondrial RNA and DNA in L6 myoblasts and HTC-IR hepatocytes cultured under low-serum conditions in the presence of insulin. The expression of the whole set of mitochondrial genes was determined using reverse transcriptase (RT)-real time PCR. Cell proliferation was assayed by the incorporation of (3)H-thymidine and myoblast differentiation was analyzed by morphological and biochemical markers of myogenesis. Low growth factor concentration in medium decreased proliferation of both cell types and induced differentiation of myoblasts. The expression of all mitochondrial genes decreased in quiescent hepatocytes whereas it increased in quiescent differentiated myotubes, as compared with proliferating cells, similarly to reflecting the expression of the insulin receptor gene, both in myoblasts and hepatocytes. The kinetics of mitochondrial RNA levels were similar to the expression patterns of two nuclear genes, subunit e of mitochondrial ATP-synthase and uncoupling protein-2; however, they did not reflect changes in mitochondrial DNA content. Insulin accelerated myogenesis and expression of both mitochondrial and nuclear genes in differentiated myotubes but not in quiescent hepatocytes. Our studies prove that myogenesis may require the orchestrated transcriptional activation of both mitochondrial and nuclear genes and provide additional evidence confirming the regulatory impact of insulin on the function of muscle mitochondria.

Animals↗

PubMed2005

Regulation of mitochondrial gene expression by energy demand in neural cells.

Mitochondrial DNA (mtDNA) encodes critical subunit proteins of the oxidative phosphorylation (OXPHOS) complex that generates ATP. This study tested the hypothesis that mitochondrial gene expression in neural cells is regulated by energy demand, as modified via stimulation of cellular sodium transport. Exposure of PC12S cells to the sodium ionophore monensin (250 nm) for 1-6 h caused a 13-60% decrease in cellular ATP (from 15 to 5 nmol per mg protein at 6 h). Levels of mitochondrial DNA-encoded mRNAs (mt-mRNAs) increased significantly (150%) within the first hour of exposure to monensin, and then decreased significantly (50%) at 3-4 h. Levels of mtDNA-encoded 12S rRNA and nuclear DNA-encoded OXPHOS subunit mRNAs were not significantly affected. Exposure of primary cerebellar neuronal cultures to the excitatory amino acid glutamate caused a similar rapid and significant increase followed by a significant decrease in cell mt-mRNA levels. The monensin-induced initial increase in mt-mRNA levels was abolished by pretreatment with actinomycin D or by reducing extracellular sodium ion concentration. The monensin-induced delayed reduction in mt-mRNA levels was accelerated in the presence of actinomycin D, and was accompanied by a 67% reduction in the half-life (from 3.6 to 1.2 h). Exposure of PC12S cells to 2-deoxy-d-glucose significantly decreased cellular ATP levels (from 14.2 to 7.1 nmol per mg protein at 8 h), and increased mt-mRNA levels. These results suggest a physiological transcriptional mechanism of regulation of mitochondrial gene expression by energy demand and a post-transcriptional regulation that is independent of energy status of the cell.

Actins↗

PubMed1997

Region specific mitochondrial gene expression in the human retina.

The human mitochondrial genome has not been previously known to differentially express specific mRNA transcripts. Results of northern analysis, using total RNA from two different retinal regions, demonstrate that there is differential expression of five mitochondrial genes. There is a correlation of regional expression of one of these differentially expressed genes with the gene responsible for the majority of cases of foveo-macular mitochondropathy. These findings suggest that there is selective control over specific mitochondrial messenger steady state levels.

Blotting, Northern↗

PubMed1989

Mitochondrial gene expression during Xenopus laevis development: a molecular study.

Mitochondrial gene expression has been analysed during embryonic development of Xenopus laevis; the relative amounts of 12S and 16S ribosomal RNAs and of most mitochondrial messenger RNAs were determined by slot-blot and Northern-blot hybridization experiments with specific mitochondrial DNA probes. The rRNA content per embryo remained constant during early development, confirming earlier results of Chase and Dawid (1972, Dev. Biol., 27, 504-518.); on the contrary, all mRNAs decreased abruptly after fertilization within a few hours (by a factor of 5-10), remained at a very low level up to the late neurula stages and increased again during organogenesis. Since the mitochondrial DNA content does not vary during this period molecular analyses as well as biological observations suggest that the mitochondrial genome is completely inactivated at the beginning of embryonic development. The amounts of rRNAs and mRNAs evolve therefore as a function of time only according to their half-lives. Mitochondrial RNA accumulation resumes subsequently with a high rate when the general transcription in the embryo is starting again, and this occurs before the resumption of DNA replication in the organelle. It appears that the Xenopus embryonic development represents a quite clear example of regulation of the mitochondrial expression at the level of transcription.

Animals↗

PubMed1989

The role of a conserved dodecamer sequence in yeast mitochondrial gene expression.

All mRNAs on the yeast mitochondrial genome terminate at a conserved dodecamer sequence 5'-AAUAAUAUUCUU-3'. We have characterized two mutants with altered dodecamers. One contains a deletion of the dodecamer at the end of the var1 gene, and the other contains two adjacent transversions in the dodecamer at the end of the reading frame of fit1, a gene within the omega+ allele of the 21S rRNA gene. In each mutant, expression of the respective gene is blocked completely. A dominant nuclear suppressor, SUV3-1, was isolated that suppresses the var1 deletion but is without effect on the fit1 dodecamer mutations. Unexpectedly, however, we found that SUV3-1 blocks expression of the wild-type fit1 allele by blocking processing at its dodecamer. SUV3-1 has pleiotropic effects on mitochondrial gene expression, affecting RNA processing, RNA stability, and translation. Our results suggest that RNA metabolism and translation may be part of a multicomponent complex within mitochondria.

Base Sequence↗

PubMed2002

Mitochondrial gene expression and ventricular fibrillation in ischemic/reperfused nondiabetic and diabetic myocardium.

We investigated the mitochondrial gene expression related to cardiac function and ventricular fibrillation (VF) in ischemic/reperfused nondiabetic and diabetic myocardium. To identify potentially more specific gene responses we performed subtractive screening, Northern blotting, and reverse transcription-polymerase chain reaction (RT-PCR) of mitochondrial genes expressed after 30 min ischemia followed by 120 min reperfusion in isolated rat hearts that showed VF or did not show VF. Cytochrome oxidase B subunit III (COXBIII) and ATP synthase subunit 6, studied and selected out of 40 mitochondrial genes by subtractive screening, showed an expression after 30 min ischemia (no VF was recorded) in both nondiabetic and diabetic subjects. Upon reperfusion, the down-regulation of these genes was only observed in fibrillated hearts. Such a reduction in signal intensity was not seen in nonfibrillated myocardium. In additional studies, nondiabetic and diabetic hearts, without the ischemia/reperfusion protocol, were subjected to electrical fibrillation, and a significant reduction in COXBIII and ATPS6 mRNA signal intensity was observed indicating that VF contributes to the down-regulation of these genes. Cardiac function (heart rate, coronary flow, aortic flow, left ventricular developed pressure) showed no correlation between the up- and down-regulation of these mitochondrial genes in both nondiabetic and diabetic ischemic/reperfused myocardium. Our data suggest that COXBIII and ATPS6 may play a critical role in arrhythmogenesis, and the stimulation of COXBIII and ATPS6 mRNA expression may prevent the development of VF in both nondiabetic and diabetic ischemic/reperfused myocardium.

Animals↗

PubMed1998

Developmental changes in heteroplasmy level and mitochondrial gene expression in a Drosophila subobscura mitochondrial deletion mutant.

Eighty percent of DNA molecules are deleted in the mitochondrial population of an adult mutant strain of D. subobscura. Both intact and deleted genomes are autonomous monomers. The heteroplasmy level, which is lower in germ tissue, increases from the oocytes (60%) to the third larval instar (83%), and is then maintained throughout the life of the fly. The mtDNA/nuclear DNA ratio is on average two-times greater in the heteroplasmic strain than in the wild-type strain, irrespective of the stage, but the cellular content of mitochondria is elevated only in the embryos and pupae of the mutant strain. The steady state concentrations (SSCs) of the transcripts affected by the deletion are greatly reduced at the larval and adult stages, and less so at the pupal stage of the mutant strain compared with the wild-type. The SSCs of these transcripts are identical in the two strains at the embryonic stage. The fusion transcript, indicating that the deleted genome is expressed, was detected at all stages. The mechanisms involved in the changes in the heteroplasmy level during the course of development and in its maintenance from the third larval instar onwards are discussed.

Animals↗

PubMed1999

Insulin-regulated mitochondrial gene expression is associated with glucose flux in human skeletal muscle.

To identify abnormally expressed genes contributing to muscle insulin resistance in type 2 diabetes, we screened the mRNA populations from normal and diabetic human skeletal muscle using cDNA differential display and isolated abnormally expressed cDNA clones of mitochondrial-encoded NADH dehydrogenase 1 (ND1), cytochrome oxidase 1, tRNA(leu), and displacement loop. We then measured mRNA expression of these mitochondrial genes using a relative quantitative polymerase chain reaction method in biopsies taken before and after an insulin clamp in 12 monozygotic twin pairs discordant for type 2 diabetes and 12 matched control subjects and in muscle biopsies taken after an insulin clamp from 13 subjects with type 2 diabetes, 15 subjects with impaired glucose tolerance, and 14 subjects with normal glucose tolerance. Insulin infusion increased mRNA expression of ND1 from 1.02 +/- 0.04 to 2.55 +/- 0.30 relative units (P < 0.001) and of cytochrome oxidase 1 from 0.80 +/- 0.01 to 1.24 +/- 0.10 relative units (P < 0.001). The ND1 response to insulin correlated with glucose uptake (r = 0.46, P = 0.002). Although the rate of insulin-mediated glucose uptake was decreased in the diabetic versus the nondiabetic twins (5.2 +/- 0.7 vs. 8.5 +/- 0.8 mg x kg(-1) fat-free mass x min(-1), P < 0.01), insulin-stimulated ND1 expression was not significantly different between them (2.4 +/- 0.5 vs. 2.7 +/- 0.5 relative units). Neither was there any significant intrapair correlation of ND1 expression between the monozygotic twins (r = -0.15, NS). We conclude that insulin upregulates mitochondrial-encoded gene expression in skeletal muscle. Given the positive correlation between ND1 expression and glucose uptake and the lack of intrapair correlation between monozygotic twins, mitochondrial gene expression may represent an adaptation to intracellular glucose flux rather than an inherited trait.

Aged↗

PubMed1994

Coordination of nuclear and mitochondrial gene expression during the development of cardiac hypertrophy in rats.

We studied the coordination of nuclear and mitochondrial gene expression during cardiac hypertrophy following aortic stenosis or thyroid hormone treatment in rats. We measured mRNA levels for representative subunits of cytochrome-c oxidase, two encoded by mitochondrial DNA and two encoded by the nucleus, as well as the levels of one mitochondrial rRNA. In both models of hypertrophy, an increase of total tissue RNA, reflecting mainly cytosolic ribosomes, accompanied the increase in ventricular weight. Relative levels of mitochondrial rRNA remained unchanged, indicating a net synthesis of mitochondrial ribosomes as well. In both models, cytochrome-c oxidase activity and nuclear-encoded mRNAs remained fairly constant, whereas levels of mitochondrial mRNAs were transiently decreased 24 h after the growth stimulus. We conclude that, in the initial phase of hypertrophy, the signal regulating the synthesis of mitochondrial rRNA is synchronized with nuclear gene expression, whereas the signal regulating mitochondrial mRNA synthesis is not. We postulate that differential regulation of mitochondrial transcription and premature termination of the polycistronic transcript (the latter giving rise to the mitochondrial rRNAs) account for the observed results.

Animals↗

PubMed2005

Mutations in MTO2 related to tRNA modification impair mitochondrial gene expression and protein synthesis in the presence of a paromomycin resistance mutation in mitochondrial 15 S rRNA.

Nuclear gene(s) have been shown to modulate the phenotypic expression of mitochondrial DNA mutations. We report here the identification and characterization of the yeast nuclear gene MTO2 encoding an evolutionarily conserved protein involved in mitochondrial tRNA modification. Interestingly, mto2 null mutants expressed a respiratory-deficient phenotype when coexisting with the C1409G mutation of mitochondrial 15 S rRNA at the very conservative site for human deafness-associated 12 S rRNA A1491G and C1409T mutations. Furthermore, the overall rate of mitochondrial translation was markedly reduced in a yeast mto2 strain in the wild type mitochondrial background, whereas mitochondrial protein synthesis was almost abolished in a yeast mto2 strain carrying the C1409G allele. The other interesting feature of mto2 mutants is the defective expression of mitochondrial genes, especially CYTB and COX1, but only when coexisting with the C1409G allele. These data strongly indicate that a product of MTO2 functionally interacts with the decoding region of 15 S rRNA, particularly at the site of the C1409G or A1491G mutation. In addition, we showed that yeast and human Mto2p localize in mitochondria. The isolated human MTO2 cDNA can partially restore the respiratory-deficient phenotype of yeast mto2 cells carrying the C1409G mutation. These functional conservations imply that human MTO2 may act as a modifier gene, modulating the phenotypic expression of the deafness-associated A1491G or C1409T mutation in mitochondrial 12 S rRNA.

Alleles↗

PubMed1986

Differential mitochondrial gene expression between slender and stumpy bloodforms of Trypanosoma brucei.

Bloodforms of Trypanosoma brucei lack complete cytochrome and Krebs cycle systems but a fully functional mitochondrial respiratory system is elaborated upon differentiation to procyclics. We previously found differential expression of some mitochondrial genes, at the level of transcript abundance, between these two life cycle stages. We report here that mitochondrial genes are also differentially expressed between the two morphological types of bloodforms. Some transcripts that are more abundant in procyclics than slender bloodforms are intermediate in abundance in stumpy bloodforms. Most major mitochondrial transcripts are more abundant in stumpy than slender bloodform RNA; some are also more abundant than in procyclic RNA. Transcripts from protein coding genes are increased in abundance to varying degrees. Treatment with difluoromethylornithine, which induces a stumpy morphology, produces transcript abundance patterns similar to those in naturally occurring stumpy bloodforms. Stumpy bloodforms also have a decrease in tubulin transcript abundance, consistent with their nondividing character and smaller flagellum. These studies suggest that molecular events associated with mitochondrial development during the differentiation from bloodforms to procyclics can be initiated in the bloodstream, and that maxicircle transcript abundances are individually modulated during the life cycle.

Animals↗

PubMed2005

Enhancement of mitochondrial gene expression in the liver of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is one of the most important autoimmune liver diseases but the etiology and pathogenesis remain unknown. In this study, we analyzed differential mRNA expression in the liver of a patient with PBC using suppression subtractive hybridization to identify overexpressed genes. Overexpression of mRNA transcripts from mitochondrial DNA was observed in the PBC liver, compared to normal liver. To explore the mechanism of increased mitochondrial transcription, we investigated the mRNA levels of nuclear DNA-encoded regulator molecules of mitochondrial gene expression in 60 liver biopsy samples from various diseases, including PBC, using competitive RT-PCR. Increased expression of mitochondrial transcriptional factor A (mtTFA) and mitochondrial nuclear respiratory factor 1 (NRF-1) mRNA was demonstrated in PBC liver compared to other liver diseases, while NRF-1 coactivator 1, PGC-1 was suppressed. Mitochondrial DNA-encoded mRNA molecules are overexpressed in the PBC liver, and this is associated with up-regulation of mitochondrial transcription factor mtTFA and its transactivator NRF-1. Further studies are needed to focus on the relevance of this perturbation of mitochondrial gene expression in the pathogenesis of PBC.

Journal Article↗

PubMed2005

Natural competence of mammalian mitochondria allows the molecular investigation of mitochondrial gene expression.

Respiration, a fundamental process in mammalian cells, requires two genomes, those of the nucleus and the mitochondrion (mtDNA). Mutations of mtDNA are being increasingly recognized in disease and may play an important role in the ageing process. Accepting the vital role of mtDNA gene products, our limited knowledge concerning the details of mitochondrial gene expression is surprising. This is, in part, due to our inability to transfect mitochondria and to manipulate their genome. There have been claims of successful DNA import into isolated organelles, but most reports lacked evidence of expression and no method has furthered our understanding of gene expression. Here, we report that mammalian mitochondria possess a natural competence for DNA import. Using five functional assays, we show imported DNA can act as templates for DNA synthesis or promoter-driven transcription, with the resultant polycistronic RNA being processed (5' and 3') and excised mt-tRNA matured. Exploiting this natural competence will allow us to explore mitochondrial gene expression in organello and provides the potential for mitochondrial transfection in vivo.

Animals↗

PubMed1995

Mitochondrial gene expression in small intestinal epithelial cells.

Most mitochondrial genes are transcribed as a single large transcript from the heavy strand of mitochondrial DNA, and are subsequently processed into the proximal mitochondrial (mt) 12 S and 16 S rRNAs, and the more distal tRNAs and mRNAs. We have shown that in intestinal epithelial biopsies the steady-state levels of mt 12 S and 16 S rRNA are an order of magnitude greater than those of mt mRNAs. Fractionation of rat small intestinal epithelial cells on the basis of their maturity has shown that the greatest ratios of 12 S mt rRNA/cytochrome b mt mRNA or 12 S mt rRNA/cytochrome oxidase I mt mRNA are found in the surface mature enterocytes, with a progressive decrease towards the crypt immature enteroblasts. Cytochrome b and cytochrome oxidase I mt mRNA levels are relatively uniform along the crypt-villus axis, but fractionation experiments showed increased levels in the crypt base. The levels of human mitochondrial transcription factor A are also greater in immature crypt enteroblasts compared with mature villus enterocytes. These results show that the relative levels of mt rRNA and mRNA are distinctly regulated in intestinal epithelial cells according to the crypt-villus position and differentiation status of the cells, and that there are higher mt mRNA and mt TFA levels in the crypts, consistent with increased transcriptional activity during mitochondrial biogenesis in the immature enteroblasts.

Adult↗

PubMed2004

An intragenic guide RNA location suggests a complex mechanism for mitochondrial gene expression in Trypanosoma brucei.

In Trypanosoma brucei, two classes of transcripts are produced from two distinct mitochondrial genome components. Guide RNAs (gRNAs) are usually minicircle encoded and exist as primary transcripts, while the maxicircle-encoded rRNAs and mRNAs are processed from a polycistronic precursor. The genes for the gRNAs gMURF2-II and gCYb(560) each have uncommon kinetoplast DNA (kDNA) locations that are not typically associated with transcription initiation events. We demonstrate that the conserved maxicircle gRNA gMURF2-II has an unusual location within the ND4 gene. This is the first report of a completely intragenic gene in kDNA. In addition, the gMURF2-II and ND4 transcripts are generated by distinctly different events; the ND4 mRNA is processed from a polycistronic precursor, while transcription of the gRNA initiates downstream of the 5' end of the ND4 gene. The gCYb(560) gene has an atypical minicircle location in that it is not flanked by the inverted repeat sequences that surround the majority of minicircle gRNA genes. Our data indicate that the mature gCYb(560) gRNA is also a primary transcript and that the 5'-end heterogeneity previously observed for this gRNA is a result of multiple transcription initiation sites and not of imprecise 5'-end processing. Together, these data indicate that gRNA genes represent individual transcription units, regardless of their genomic context, and suggest a complex mechanism for mitochondrial gene expression in T. brucei.

Animals↗

PubMed1998

Chromosomal locations of three human nuclear genes (RPSM12, TUFM, and AFG3L1) specifying putative components of the mitochondrial gene expression apparatus.

We have mapped the chromosomal locations of three human nuclear genes for putative components of the apparatus of mitochondrial gene expression, using a combination of in situ hybridization and interspecies hybrid mapping. The genes RPMS12 (mitoribosomal protein S12, a conserved protein component of the mitoribosomal accuracy center), TUFM (mitochondrial elongation factor EF-Tu), and AFG3L1 (similar to the yeast genes Afg3 and Rca1 involved in the turnover of mistranslated or misfolded mtDNA-encoded polypeptides) were initially characterized by a combination of database sequence analysis, PCR, cloning, and DNA sequencing. RPMS12 maps to chromosome 19q13.1, close to the previously mapped gene for autosomal dominant hearing loss DFNA4. The TUFM gene is located on chromosome 16p11.2, with a putative pseudogene or variant (TUFML) located very close to the centromere of chromosome 17. AFG3L1 is located on chromosome 16q24, very close to the telomere. By virtue of their inferred functions in mitochondria, these genes should be regarded as candidates of disorders sharing features with mitochondrial disease syndromes, such as sensorineural deafness, diabetes, and retinopathy.

ATPases Associated with Diverse Cellular Activitie↗

PubMed2006

Homeotic-like modification of stamens to petals is associated with aberrant mitochondrial gene expression in cytoplasmic male sterile Ogura Brassica juncea.

We have previously reported correction of severe leaf chlorosis in the cytoplasmic male sterile Ogura (also called Ogu) Brassica juncea line carrying Ogura cytoplasm by plastid substitution via protoplast fusion. Two cybrids obtained from the fusion experiment, Og1 and Og2, were green and carried the plastid genome of B. juncea cv. RLM198. While Og1 displayed normal flower morphology comparable to that of its euplasmic B. juncea counterpart except for sterile anthers, Og2 retained homeotic-like floral modification of stamens to petal-like structures and several other floral deformities observed in the chlorotic (Ogu) B. juncea cv. RLM198 (or OgRLM). With respect to the mitochondrial genome, Og1 showed 81% genetic similarity to the fertile cultivar RLM while Og2 showed 93% similarity to OgRLM. In spite of recombination and rearrangements in the mitochondrial genomes in the cybrids, expression patterns of 10 out of 11 mitochondrial genes were similar in all the three CMS lines; the only exception was atp6, whose expression was altered. While Og1 showed normal atp6 transcript similar to that in RLM, in Og2 and OgRLM weak expression of a longer transcript was detected. These results suggest that the homeotic-like changes in floral patterning leading to petaloid stamens in Og2 and OgRLM may be associated with aberrant mitochondrial gene expression.

Blotting, Northern↗