Mithochondrial biogenesis: recent developments and insights

1988 ◽  
Vol 319 (1193) ◽  
pp. 85-95
Keyword(s):  
Rna Splicing ◽  
Mitochondrial Genes ◽  
Pivotal Role ◽  
Mitochondrial Proteins ◽  
Rna Catalysis ◽  
Expression Of Genes ◽  
Recent Developments ◽  
Self Splicing ◽  
Shed Light

Biosynthesis of a functional mitochondrion requires the coordinate expression of genes in both mitochondrial and nuclear DNAs. In yeast, three mitochondrial genes are split and RNA splicing plays a pivotal role in their expression. The recent finding that some introns are capable of self-splicing activity in vitro has permitted analysis of the mechanisms involved in RNA catalysis and may eventually shed light on the evolution of splicing mechanisms in general. Most mitochondrial proteins are encoded by nuclear genes, synthesized in the cytoplasm and imported by the organelle. The availability of cloned genes coding for several constituent subunits of the ubiquinol-cytochrome c reductase, which are imported by mitochondria, has allowed study of selected steps in the addressing of proteins to mitochondria and their intercompartmental sorting within the organelle. Recent developments are discussed.

Ribozymes, the first 20 years

2002 ◽  
Vol 30 (6) ◽  
pp. 1162-1166 ◽  
Author(s):  
T. R. Cech
Keyword(s):  
In Vitro Selection ◽  
Tertiary Structure ◽  
Catalytic Rna ◽  
Rna Catalysis ◽  
X Ray Crystallography ◽  
Mechanistic Analysis ◽  
Self Splicing ◽  
Secondary And Tertiary Structure

In 1982 we reported the first catalytic RNA or ribozyme: the self-splicing intron of the Tetrahymena pre-rRNA. Additional examples of natural ribozymes were soon found, and research in the field focused on their enzymic mechanism and secondary and tertiary structure. Ribozymes identified through in vitro selection extended the repertoire of RNA catalysis. Two directions of current and future interest are the determination of atomic-resolution structures of large ribozymes by X-ray crystallography and the structural and mechanistic analysis of complexes of ribozymes with protein facilitators of their activity.

RNA splicing in neurospora mitochondria: Self-splicing of a mitochondrial intron in vitro

Cell ◽  
1984 ◽  
Vol 39 (3) ◽  
pp. 631-641 ◽  
Author(s):  
Gian Garriga ◽  
Alan M. Lambowitz
Keyword(s):  
Rna Splicing ◽  
Self Splicing

scholarly journals Spliceosomal Prp8 intein at the crossroads of protein and RNA splicing

2018 ◽  
Author(s):  
Cathleen M. Green ◽  
Zhong Li ◽  
Olga Novikova ◽  
Valjean R. Bacot-Davis ◽  
Fenghan Gao ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Rna Splicing ◽  
Fungal Pathogen ◽  
Rna Catalysis ◽  
Protein Splicing ◽  
Reporter Assay ◽  
Structural Homology ◽  
Biologically Relevant ◽  
Human Fungal Pathogen ◽  
Self Splicing

The spliceosome is a large ribonucleoprotein complex that removes introns from pre-mRNAs. At its functional core lies the essential Prp8 protein. Across diverse eukaryotes, this protein cofactor of RNA catalysis harbors a self-splicing element, called an intein. Inteins in Prp8 are extremely pervasive and are found at seven different sites in various species. Here, we focus on the Prp8 intein from Cryptococcus neoformans, a human fungal pathogen. We solved the crystal structure of this intein, revealing structural homology among self-splicing sequences in eukaryotes, including Hedgehog protein. Working with the C. neoformans Prp8 intein in a reporter assay, we find that the biologically relevant divalent metals copper and zinc inhibit intein splicing, albeit by two different mechanisms. Copper likely stimulates reversible modifications on a catalytically important cysteine, whereas zinc binds via the same critical cysteine with a Kd of ~1 nM. An intein-containing Prp8 precursor model is presented, suggesting that metal-induced protein splicing inhibition would disturb function of both Prp8 and the spliceosome. These results indicate that Prp8 protein splicing can be modulated, and that this could alter spliceosome function and RNA splicing under specific conditions.

Abstract 355: In Vivo Targeting Of GTF2B Selectively Inhibits Transcription Of Cardiomyopathy-related Genes And Partially Blunts Development Of Cardiac Hypertrophy

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Danish Sayed ◽  
Zhi Yang ◽  
Minzhen He ◽  
Maha Abdellatif
Keyword(s):  
Rna Polymerase Ii ◽  
Rna Splicing ◽  
De Novo ◽  
Transcriptional Profiling ◽  
Essential Genes ◽  
Pol Ii ◽  
Expression Of Genes ◽  
Essential Components

Transcriptional profiling of cardiac genome during hypertrophy identified two categories of genes with distinct modes of regulation. The first set of genes involved in the cells essential functions (e.g. RNA splicing) and whose transcription is expected to be incremental and contribute to the increasing cardiac mass is regulated by promoter clearance of RNA polymerase II (pol II). On the other hand, the second set that include genes with specialized function and show a robust increase in expression upon growth stimulus (cytoskeletal, extracellular matrix) are regulated by de novo pol II recruitment to promoters. Our goal was to identify the transcriptional mechanisms that distinguish these two sets of genes and then to selectively inhibit those that participate in contractile dysfunction, while preserving the expression of genes necessary for essential functions. General Transcription factor IIB (GTF2B), is one of the essential components of transcription machinery and is required for pol II recruitment. Thus, we hypothesized that inhibition of GTF2B would result in inhibition of only the specialized genes, sparing the essential genes. Our in vitro results with shRNA mediated inhibition of GTF2B in hypertrophying neonatal myocytes showed decreased expression of genes that required de novo pol II recruitment for transcription (eg. ACTA1), while no change was observed in the genes regulated by promoter clearance of pol II (Vdac1). Similarly, preliminary results with in vivo knockdown of GTF2B (~80% reduction in mRNA and ~36% in protein) via intravenous injection of modified antisense oligo in mice subjected to transaortic coarctation (TAC) showed inhibition of only cardiomyopathy-related genes that require pol II recruitment (ANF), while expression of essential genes (Vdac1) remained unchanged. Inhibition of GTF2B restricted increase in TAC-induced heart wt to 9%, compared to 29% in TAC hearts with control oligo. Echocardiography showed partial normalization of ejection fraction with GTF2B inhibitor during TAC from 61.5% to 66.4% compared to sham hearts with 71%. Thus, we conclude that by targeting GTF2B we can selectively restrict the expression of detrimental genes during hypertrophy, thereby delaying the onset of cardiac dysfunction and failure

Anti-Diabetic Activity of a Mineraloid Isolate, in vitro and in Genetically Diabetic Mice

2011 ◽  
Vol 81 (1) ◽  
pp. 34-42 ◽  
Author(s):  
Joel Deneau ◽  
Taufeeq Ahmed ◽  
Roger Blotsky ◽  
Krzysztof Bojanowski
Keyword(s):  
Dna Microarrays ◽  
Human Fibroblasts ◽  
Diabetic Animal ◽  
In Vitro Tests ◽  
Diabetic Mice ◽  
Fossil Material ◽  
Expression Of Genes ◽  
Enhanced Expression ◽  
Genetically Diabetic Mice

Type II diabetes is a metabolic disease mediated through multiple molecular pathways. Here, we report anti-diabetic effect of a standardized isolate from a fossil material - a mineraloid leonardite - in in vitro tests and in genetically diabetic mice. The mineraloid isolate stimulated mitochondrial metabolism in human fibroblasts and this stimulation correlated with enhanced expression of genes coding for mitochondrial proteins such as ATP synthases and ribosomal protein precursors, as measured by DNA microarrays. In the diabetic animal model, consumption of the Totala isolate resulted in decreased weight gain, blood glucose, and glycated hemoglobin. To our best knowledge, this is the first description ever of a fossil material having anti-diabetic activity in pre-clinical models.

Contributory Fault under International Law: A Gateway for Human Rights in ISDS?

2020 ◽  
Author(s):  
Farouk El-Hosseny ◽  
Patrick Devine
Keyword(s):  
Human Rights ◽  
International Law ◽  
Multinational Enterprises ◽  
Indigenous Rights ◽  
Business And Human Rights ◽  
Investment Treaty ◽  
Recent Developments ◽  
The Government ◽  
Bear Creek ◽  
Shed Light

Abstract The intersection between foreign investment and human rights is gaining attention, as is evident from an increasing number of investment treaty awards analysing legal issues relating to human rights. In the recent International Centre for the Settlement of Investment Disputes (ICSID) arbitration of Bear Creek v Peru, Philippe Sands QC posited, in a dissenting opinion, that the investor’s contribution to events—ie protests against its allegedly adverse environmental impact and disregard of indigenous rights, namely resulting from its ‘inability to obtain a “social licence”’—which led to the unlawful expropriation of its investment, was ‘significant and material’. He further noted that the investor’s ‘responsibilities are no less than those of the government’ and found that damages should thus be reduced. Last year, the Netherlands adopted a new model bilateral investment treaty (BIT), which allows tribunals to ‘take into account non-compliance by the investor with the UN Guiding Principles on Business and Human Rights and the OECD Guidelines for Multinational Enterprises’ when assessing damages. These recent developments shed light on how states and tribunals, as part of their decision-making process, can take into account human rights in practice, and crucially in respect of damages analyses. By first dissecting the concept of contributory fault, then shedding light on the intersection of investment treaty law and human rights, as elucidated in recent jurisprudence, this article questions whether there now exists a gateway for human rights obligations (soft or hard) in the investment treaty arbitration realm through the concept of contributory fault.

scholarly journals The methyltransferase SETD2 couples transcription and splicing by engaging mRNA processing factors through its SHI domain

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Saikat Bhattacharya ◽  
Michaella J. Levy ◽  
Ning Zhang ◽  
Hua Li ◽  
Laurence Florens ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Rna Binding ◽  
Mrna Processing ◽  
Key Factors ◽  
Pol Ii ◽  
Mrna Transcripts ◽  
Hnrnp Protein ◽  
Processing Factors

AbstractHeterogeneous ribonucleoproteins (hnRNPs) are RNA binding molecules that are involved in key processes such as RNA splicing and transcription. One such hnRNP protein, hnRNP L, regulates alternative splicing (AS) by binding to pre-mRNA transcripts. However, it is unclear what factors contribute to hnRNP L-regulated AS events. Using proteomic approaches, we identified several key factors that co-purify with hnRNP L. We demonstrate that one such factor, the histone methyltransferase SETD2, specifically interacts with hnRNP L in vitro and in vivo. This interaction occurs through a previously uncharacterized domain in SETD2, the SETD2-hnRNP Interaction (SHI) domain, the deletion of which, leads to a reduced H3K36me3 deposition. Functionally, SETD2 regulates a subset of hnRNP L-targeted AS events. Our findings demonstrate that SETD2, by interacting with Pol II as well as hnRNP L, can mediate the crosstalk between the transcription and the splicing machinery.

scholarly journals The Differential Metabolomes in Cumulus and Mural Granulosa Cells from Human Preovulatory Follicles

2021 ◽  
Author(s):  
Er-Meng Gao ◽  
Bongkoch Turathum ◽  
Ling Wang ◽  
Di Zhang ◽  
Yu-Bing Liu ◽  
...  
Keyword(s):  
Oocyte Maturation ◽  
Granulosa Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Cumulus Cells ◽  
Cholesterol Transport ◽  
Vitro Fertilization ◽  
Expression Of Genes ◽  
Preovulatory Follicles ◽  
Morphological Differences

AbstractThis study evaluated the differences in metabolites between cumulus cells (CCs) and mural granulosa cells (MGCs) from human preovulatory follicles to understand the mechanism of oocyte maturation involving CCs and MGCs. CCs and MGCs were collected from women who were undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment. The differences in morphology were determined by immunofluorescence. The metabolomics of CCs and MGCs was measured by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) followed by quantitative polymerase chain reaction (qPCR) and western blot analysis to further confirm the genes and proteins involved in oocyte maturation. CCs and MGCs were cultured for 48 h in vitro, and the medium was collected for detection of hormone levels. There were minor morphological differences between CCs and MGCs. LC-MS/MS analysis showed that there were differences in 101 metabolites between CCs and MGCs: 7 metabolites were upregulated in CCs, and 94 metabolites were upregulated in MGCs. The metabolites related to cholesterol transport and estradiol production were enriched in CCs, while metabolites related to antiapoptosis were enriched in MGCs. The expression of genes and proteins involved in cholesterol transport (ABCA1, LDLR, and SCARB1) and estradiol production (SULT2B1 and CYP19A1) was significantly higher in CCs, and the expression of genes and proteins involved in antiapoptosis (CRLS1, LPCAT3, and PLA2G4A) was significantly higher in MGCs. The level of estrogen in CCs was significantly higher than that in MGCs, while the progesterone level showed no significant differences. There are differences between the metabolomes of CCs and MGCs. These differences may be involved in the regulation of oocyte maturation.

The Use of Biomarkers as Alternatives to Current Animal Tests on Food Chemicals

1998 ◽  
Vol 26 (4) ◽  
pp. 421-480
Author(s):  
Krys Bottrill
Keyword(s):  
Animal Studies ◽  
Developmental Toxicity ◽  
Reproductive Toxicity ◽  
In Vitro Test ◽  
Animal Testing ◽  
Dietary Biomarkers ◽  
Recent Developments ◽  
Mechanistic Basis ◽  
The Three Rs

Recent developments in biomarkers relating to the interrelationship of diet, disease and health were surveyed. Most emphasis was placed on biomarkers of deleterious effects, since these are of greatest relevance to the subject of this review. The area of greatest activity was found to be that relating to biomarkers of mutagenic, genotoxic and carcinogenic effects. This is also one of the major areas of concern in considerations of the beneficial and deleterious effects of dietary components, and also the area in which regulatory testing requires studies of the longest duration. A degree of progress has also been made in the identification and development of biomarkers relating to certain classes of target organ toxicity. Biomarkers for other types of toxicity, such as immunotoxicity, neurotoxicity, reproductive toxicity and developmental toxicity, are less developed, and further investigation in these areas is required before a comprehensive biomarker strategy can be established. A criticism that recurs constantly in the biomarker literature is the lack of standardisation in the methods used, and the lack of reference standards for the purposes of validation and quality control. It is encouraging to note the growing acknowledgement of the need for validation of biomarkers and biomarker assays. Some validation studies have already been initiated. This review puts forward proposals for criteria to be used in biomarker validation. More discussion on this subject is required. It is concluded that the use of biomarkers can, in some cases, facilitate the implementation of the Three Rs with respect to the testing of food chemicals and studies on the effects of diet on health. The greatest potential is seen to be in the refinement of animal testing, in which biomarkers could serve as early and sensitive endpoints, in order to reduce the duration of the studies and also reduce the number of animals required. Biomarkers could also contribute to establishing a mechanistic basis for in vitro test systems and to facilitating their validation and acceptance. Finally, the increased information that could result from the incorporation of biomarker determinations into population studies could reduce the need for supplementary animal studies. This review makes a number of recommendations concerning the prioritisation of future activities on dietary biomarkers in relation to the Three Rs. It is emphasised, however, that further discussions will be required among toxicologists, epidemiologists and others researching the relationship between diet and health.

Sign in / Sign up

Export Citation Format

Share Document