scholarly journals Blackout in the powerhouse: clinical phenotypes associated with defects in the assembly of OXPHOS complexes and the mitoribosome

2020 ◽  
Vol 477 (21) ◽  
pp. 4085-4132
Author(s):  
Daniella H. Hock ◽  
David R. L. Robinson ◽  
David A. Stroud
Keyword(s):  
Mitochondrial Disease ◽  
Mitochondrial Diseases ◽  
Basic Research ◽  
Post Translational Modification ◽  
Mitochondrial Ribosomes ◽  
Heterogenous Group ◽  
Mitochondrial Ribosome ◽  
Genes Encoding ◽  
Severity Of The Disease ◽  
Almost All

Mitochondria produce the bulk of the energy used by almost all eukaryotic cells through oxidative phosphorylation (OXPHOS) which occurs on the four complexes of the respiratory chain and the F1–F0 ATPase. Mitochondrial diseases are a heterogenous group of conditions affecting OXPHOS, either directly through mutation of genes encoding subunits of OXPHOS complexes, or indirectly through mutations in genes encoding proteins supporting this process. These include proteins that promote assembly of the OXPHOS complexes, the post-translational modification of subunits, insertion of cofactors or indeed subunit synthesis. The latter is important for all 13 of the proteins encoded by human mitochondrial DNA, which are synthesised on mitochondrial ribosomes. Together the five OXPHOS complexes and the mitochondrial ribosome are comprised of more than 160 subunits and many more proteins support their biogenesis. Mutations in both nuclear and mitochondrial genes encoding these proteins have been reported to cause mitochondrial disease, many leading to defective complex assembly with the severity of the assembly defect reflecting the severity of the disease. This review aims to act as an interface between the clinical and basic research underpinning our knowledge of OXPHOS complex and ribosome assembly, and the dysfunction of this process in mitochondrial disease.

scholarly journals Modulating Mitophagy in Mitochondrial Disease

2019 ◽  
Vol 25 (40) ◽  
pp. 5597-5612 ◽  
Author(s):  
Eszter Dombi ◽  
Heather Mortiboys ◽  
Joanna Poulton
Keyword(s):  
Signaling Pathways ◽  
Mitochondrial Disease ◽  
Coenzyme Q ◽  
Mitochondrial Diseases ◽  
Degradation Pathway ◽  
Selective Degradation ◽  
Genes Encoding ◽  
Phosphoinositide 3 Kinase ◽  
Quality Control Mechanism ◽  
Amp Activated Protein Kinase

Mitochondrial diseases may result from mutations in the maternally-inherited mitochondrial DNA (mtDNA) or from mutations in nuclear genes encoding mitochondrial proteins. Their bi-genomic nature makes mitochondrial diseases a very heterogeneous group of disorders that can present at any age and can affect any type of tissue. The autophagic-lysosomal degradation pathway plays an important role in clearing dysfunctional and redundant mitochondria through a specific quality control mechanism termed mitophagy. Mitochondria could be targeted for autophagic degradation for a variety of reasons including basal turnover for recycling, starvation induced degradation, and degradation due to damage. While the core autophagic machinery is highly conserved and common to most pathways, the signaling pathways leading to the selective degradation of damaged mitochondria are still not completely understood. Type 1 mitophagy due to nutrient starvation is dependent on PI3K (phosphoinositide 3-kinase) for autophagosome formation but independent of mitophagy proteins, PINK1 (PTEN-induced putative kinase 1) and Parkin. Whereas type 2 mitophagy that occurs due to damage is dependent on PINK1 and Parkin but does not require PI3K. Autophagy and mitophagy play an important role in human disease and hence could serve as therapeutic targets for the treatment of mitochondrial as well as neurodegenerative disorders. Therefore, we reviewed drugs that are known modulators of autophagy (AICAR and metformin) and may affect this by activating the AMP-activated protein kinase signaling pathways. Furthermore, we reviewed the data available on supplements, such as Coenzyme Q and the quinone idebenone, that we assert rescue increased mitophagy in mitochondrial disease by benefiting mitochondrial function.

scholarly journals AB0058 ASSOCIATION BETWEEN HLA-DRB1*04:01, RHEUMATOID NODULES AND PARTICULAR EPITOPES OF CITRULLINATED FIBRIN IN PATIENTS WITH RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1061.1-1061
Author(s):  
G. Larid ◽  
M. Pancarte ◽  
G. Offer ◽  
C. Clavel ◽  
M. Martin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Amino Acid ◽  
Antigen Processing ◽  
Rheumatoid Factors ◽  
Post Translational Modification ◽  
Human Fibrinogen ◽  
Rheumatoid Nodules ◽  
Genes Encoding ◽  
High Level ◽  
Almost All

Background:Rheumatoid arthritis (RA) is associated with HLA-DRB1 genes encoding the shared epitope (SE), a 5 amino acid motive. RA is usually preceded by the emergence of anti-citrullinated protein antibodies (ACPAs) detected by anti-CCP2 tests. Citrullin is a neutral amino acid resulting from post translational modification of arginin by Peptidyl Arginyl Deiminases (PADs). ACPAs recognize epitopes from citrullinated human fibrinogen (Fib-cit) and can be specifically detected by the AhFibA assay. Five peptides derived from Fib-cit together represent almost all of the epitopes recognized by patients with ACPA-positive RA: β60–74cit, α36–50cit, α621–635cit, α501–515cit and α171–185cit. As RA is a pleiomorphic disease, whose evolution is difficult to predict, the use of antibody fine specificity as a marker of clinical phenotypes has become a major challenge.Objectives:Our objective was to study whether clinical characteristics and HLA-DRB1 genetic background were associated with a specific reactivity against these epitopes.Methods:184 ACPA positive RA patients fulfilling the 2010 ACR/EULAR criteria were studied. Patients characteristics, including HLA-DRB1 genotype, were collected from their medical files. Anti-CCP2, AhFibA, Rheumatoid Factors (RF), and antibodies against the five major Fib-cit peptides were analyzed using ELISA assays.Results:Anti-CCP2 and AhFibA titres were strongly correlated (rs: 0.7037; p = 5.69x10-29, Pearson’s). Anti-α505-515cit antibodies were associated with HLA-DRB1*04:01 (OR = 5.52 [2.00 – 13.64]; p = 0.0003). High level anti-α505-515cit antibodies were significantly associated with rheumatoid nodules (OR = 2.71 [1.00 – 7.16], p= 0.044). Anti α501–515cit antibodies were associated with RF (OR=2.31 [1.10 – 4.78], p= 0.026).Conclusion:Immune complexes containing anti-α501–515cit antibodies and rheumatoid factors might be involved in the development of rheumatoid nodules on the HLA-DRB1*04:01 background. These findings highlight the role played by the HLA-DRB1*04:01 molecule and its rapid intracellular route into the lysosomes, enabling original antigen processing. Finally, purifying these epitope specific antibodies might be a new therapeutic opportunity for rheumatoid nodules.Disclosure of Interests:None declared

scholarly journals In Rheumatoid Arthritis Patients, HLA-DRB1*04:01 and Rheumatoid Nodules Are Associated With ACPA to a Particular Fibrin Epitope

2021 ◽  
Vol 12 ◽  
Author(s):  
Guillaume Larid ◽  
Mikael Pancarte ◽  
Géraldine Offer ◽  
Cyril Clavel ◽  
Marielle Martin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Amino Acid ◽  
Patient Characteristics ◽  
Post Translational Modification ◽  
Rheumatoid Nodules ◽  
Genes Encoding ◽  
Therapeutic Opportunity ◽  
Specific Reactivity ◽  
High Level ◽  
Almost All

ObjectivesRheumatoid arthritis (RA) is associated with HLA-DRB1 genes encoding the shared epitope (SE), a 5-amino acid motive. RA is usually preceded by the emergence of anti-citrullinated protein/peptide antibodies (ACPAs). Citrulline is a neutral amino acid resulting from post-translational modification of arginine involved in peptidic bounds (arginyl residue) by PeptidylArginine Deiminases (PADs). ACPAs recognize epitopes from citrullinated human fibrin(ogen) (hFib) and can be specifically detected by the AhFibA assay. Five citrullinated peptides derived from hFib together represent almost all of the epitopes recognized by patients with ACPA-positive RA, namely: α36–50cit, α171–185cit, α501–515cit, α621–635cit, and β60–74cit. The use of antibody fine specificities as markers of clinical phenotypes has become a major challenge. Our objective was to study whether RA clinical characteristics and HLA-DRB1 genetic background were associated with a specific reactivity against the epitopes borne by the five peptides.Methods184 ACPA-positive RA patients fulfilling the 2010 ACR/EULAR criteria were studied. Patient characteristics including HLA-DRB1 genotype, were collected from their medical files. Anti-CCP2 antibodies, AhFibA, and antibodies against the five citrullinated hFib (hFib-cit) peptides were analyzed by ELISA.ResultsAnti-α505-515cit antibodies were associated with HLA-DRB1*04:01 (OR = 5.52 [2.00 – 13.64]; p = 0.0003). High level anti-α505-515cit antibodies were associated with rheumatoid nodules (OR = 2.71 [1.00 – 7.16], p= 0.044).ConclusionImmune complexes containing anti-α501-515cit antibodies and rheumatoid factors might be involved in the development of rheumatoid nodules on the HLA-DRB1*04:01 background. Apheresis of these epitope-specific antibodies might be a new therapeutic opportunity for patients with rheumatoid nodules.

scholarly journals Diagnosing pediatric mitochondrial disease: lessons from 2,000 exomes

2021 ◽  
Author(s):  
Sarah L Stenton ◽  
Masaru Shimura ◽  
Dorota Piekutowska-Abramczuk ◽  
Peter Freisinger ◽  
Felix Distelmaier ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Molecular Diagnosis ◽  
Mitochondrial Disease ◽  
Mitochondrial Diseases ◽  
Improve Patient Care ◽  
Disease Genes ◽  
Common Denominator ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Genes Encoding

Background: The spectrum of mitochondrial disease is genetically and phenotypically diverse, resulting from pathogenic variants in over 400 genes, with aerobic energy metabolism defects as a common denominator. Such heterogeneity poses a significant challenge in making an accurate diagnosis, critical for precision medicine. Methods: In an international collaboration initiated by the European Network for Mitochondrial Diseases (GENOMIT) we recruited 2,023 pediatric patients at 11 specialist referral centers between October 2010 and January 2021, accumulating exome sequencing and HPO-encoded phenotype data. An exome-wide search for variants in known and potential novel disease genes, complemented by functional studies, followed ACMG guidelines. Results: 1,109 cases (55%) received a molecular diagnosis, of which one fifth have potential disease-modifying treatments (236/1,109, 21%). Functional studies enabled diagnostic uplift from 36% to 55% and discovery of 62 novel disease genes. Pathogenic variants were identified within genes encoding mitochondrial proteins or RNAs in 801 cases (72%), while, given extensive phenotype overlap, the remainder involved proteins targeted to other cellular compartments. To delineate genotype-phenotype associations, our data was complemented with registry and literature data to develop GENOMITexplorer, an open access resource detailing patient- (n=3,940), gene- (n=427), and variant-level (n=1,492) associations (prokischlab.github.io/GENOMITexplorer/). Conclusions: Reaching a molecular diagnosis was essential for implementation of precision medicine and clinical trial eligibility, underlining the need for genome-wide screening given inability to accurately define mitochondrial diseases clinically. Key to diagnostic success were functional studies, encouraging early acquisition of patient-derived tissues and routine integration of high-throughput functional data to improve patient care by uplifting diagnostic rate.

scholarly journals Structural basis of GTPase-mediated mitochondrial ribosome biogenesis and recycling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hauke S. Hillen ◽  
Elena Lavdovskaia ◽  
Franziska Nadler ◽  
Elisa Hanitsch ◽  
Andreas Linden ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Ribosomal Subunit ◽  
Structural Basis ◽  
Peptidyl Transferase ◽  
Mitochondrial Ribosomes ◽  
Mitochondrial Ribosome ◽  
In Vitro Reconstitution

AbstractRibosome biogenesis requires auxiliary factors to promote folding and assembly of ribosomal proteins and RNA. Particularly, maturation of the peptidyl transferase center (PTC) is mediated by conserved GTPases, but the molecular basis is poorly understood. Here, we define the mechanism of GTPase-driven maturation of the human mitochondrial large ribosomal subunit (mtLSU) using endogenous complex purification, in vitro reconstitution and cryo-EM. Structures of transient native mtLSU assembly intermediates that accumulate in GTPBP6-deficient cells reveal how the biogenesis factors GTPBP5, MTERF4 and NSUN4 facilitate PTC folding. Addition of recombinant GTPBP6 reconstitutes late mtLSU biogenesis in vitro and shows that GTPBP6 triggers a molecular switch and progression to a near-mature PTC state. Additionally, cryo-EM analysis of GTPBP6-treated mature mitochondrial ribosomes reveals the structural basis for the dual-role of GTPBP6 in ribosome biogenesis and recycling. Together, these results provide a framework for understanding step-wise PTC folding as a critical conserved quality control checkpoint.

scholarly journals Markers of Genetic Variation in Blue Gourami (Trichogaster trichopterus) as a Model for Labyrinth Fish

Biology ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 228
Author(s):  
Gad Degani ◽  
Isana Veksler-Lublinsky ◽  
Ari Meerson
Keyword(s):  
Growth Hormone ◽  
Genetic Variation ◽  
Genetic Markers ◽  
Basic Research ◽  
Coi Gene ◽  
12S Rrna ◽  
Rrna Gene ◽  
Somatotropic Axis ◽  
Genes Encoding ◽  
Growth And Reproduction

Markers of genetic variation between species are important for both applied and basic research. Here, various genes of the blue gourami (Trichogaster trichopterus, suborder Anabantoidei, a model labyrinth fish), many of them involved in growth and reproduction, are reviewed as markers of genetic variation. The genes encoding the following hormones are described: kisspeptins 1 and 2, gonadotropin-releasing hormones 1, 2, and 3, growth hormone, somatolactin, prolactin, follicle- stimulating hormone and luteinizing hormone, as well as mitochondrial genes encoding cytochrome b and 12S rRNA. Genetic markers in blue gourami, representing the suborder Anabantoidei, differ from those in other bony fishes. The sequence of the mitochondrial cytochrome c oxidase subunit 1 (COI) gene of blue gourami is often used to study the Anabantoidei suborder. Among the genes involved in controlling growth and reproduction, the most suitable genetic markers for distinguishing between species of the Anabantoidei have functions in the hypothalamic–pituitary–somatotropic axis: pituitary adenylate cyclase-activating polypeptide and growth hormone, and the 12S rRNA gene.

scholarly journals Epilepsy in Mitochondrial Diseases—Current State of Knowledge on Aetiology and Treatment

Children ◽  
2021 ◽  
Vol 8 (7) ◽  
pp. 532
Author(s):  
Dorota Wesół-Kucharska ◽  
Dariusz Rokicki ◽  
Aleksandra Jezela-Stanek
Keyword(s):  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Clinical Picture ◽  
Poor Prognosis ◽  
Treatment Options ◽  
Mitochondrial Diseases ◽  
Energy Deficit ◽  
Atp Production ◽  
Current State

Mitochondrial diseases are a heterogeneous group of diseases resulting from energy deficit and reduced adenosine triphosphate (ATP) production due to impaired oxidative phosphorylation. The manifestation of mitochondrial disease is usually multi-organ. Epilepsy is one of the most common manifestations of diseases resulting from mitochondrial dysfunction, especially in children. The onset of epilepsy is associated with poor prognosis, while its treatment is very challenging, which further adversely affects the course of these disorders. Fortunately, our knowledge of mitochondrial diseases is still growing, which gives hope for patients to improve their condition in the future. The paper presents the pathophysiology, clinical picture and treatment options for epilepsy in patients with mitochondrial disease.

scholarly journals Mirolase, a novel subtilisin-like serine protease from the periodontopathogen Tannerella forsythia

2015 ◽  
Vol 396 (3) ◽  
pp. 261-275 ◽  
Author(s):  
Miroslaw Ksiazek ◽  
Abdulkarim Y. Karim ◽  
Danuta Bryzek ◽  
Jan J. Enghild ◽  
Ida B. Thøgersen ◽  
...  
Keyword(s):  
Serine Protease ◽  
Calcium Ions ◽  
Enzyme Stability ◽  
Amidolytic Activity ◽  
Tannerella Forsythia ◽  
Calcium Dependent ◽  
Genes Encoding ◽  
Mature Enzyme ◽  
Almost All ◽  
Unique Mechanism

Abstract The genome of Tannerella forsythia, an etiological factor of chronic periodontitis, contains several genes encoding putative proteases. Here, we characterized a subtilisin-like serine protease of T. forsythia referred to as mirolase. Recombinant full-length latent promirolase [85 kDa, without its signal peptide (SP)] processed itself through sequential autoproteolytic cleavages into a mature enzyme of 40 kDa. Mirolase latency was driven by the N-terminal prodomain (NTP). In stark contrast to almost all known subtilases, the cleaved NTP remained non-covalently associated with mirolase, inhibiting its proteolytic, but not amidolytic, activity. Full activity was observed only after the NTP was gradually, and fully, degraded. Both activity and processing was absolutely dependent on calcium ions, which were also essential for enzyme stability. As a consequence, both serine protease inhibitors and calcium ions chelators inhibited mirolase activity. Activity assays using an array of chromogenic substrates revealed that mirolase specificity is driven not only by the substrate-binding subsite S1, but also by other subsites. Taken together, mirolase is a calcium-dependent serine protease of the S8 family with the unique mechanism of activation that may contribute to T. forsythia pathogenicity by degradation of fibrinogen, hemoglobin, and the antimicrobial peptide LL-37.

Semisynthetic triazoles as an approach in the discovery of Novel Lead Compounds

2021 ◽  
Vol 25 ◽  
Author(s):  
Pedro Alves Bezerra Morais ◽  
Carla Santana Francisco ◽  
Heberth de Paula ◽  
Rayssa Ribeiro ◽  
Mariana Alves Eloy ◽  
...  
Keyword(s):  
Natural Products ◽  
Medicinal Chemistry ◽  
Chemical Space ◽  
Biological Activities ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Modern Drug ◽  
New Chemical Entities ◽  
Almost All ◽  
The 19Th Century

: Historically, the medicinal chemistry is concerned with the approach of organic chemistry to new drug synthesis. Considering the fruitful collections of new molecular entities, the dedicated efforts for medicinal chemistry are rewarding. Planning and search of new and applicable pharmacologic therapies involve the altruistic nature of the scientists. Since the 19th century, notoriously the application of isolated and characterized plant-derived compounds in modern drug discovery and in various stages of clinical development highlight its viability and significance. Natural products influence a broad range of biological processes, covering transcription, translation, and post-translational modification and being effective modulators of almost all basic cellular processes. The research of new chemical entities through “click chemistry” continuously opens up a map for the remarkable exploration of chemical space in towards leading natural products optimization by structure-activity relationship. Finally, here in this review, we expect to gather a broad knowledge involving triazolic natural products derivatives, synthetic routes, structures, and their biological activities.

scholarly journals Non-Penicillin-Susceptible Streptococcus suis Isolated from Humans

Pathogens ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1178
Author(s):  
Nichari Bamphensin ◽  
Peechanika Chopjitt ◽  
Rujirat Hatrongjit ◽  
Parichart Boueroy ◽  
Nahuel Fittipaldi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Antimicrobial Resistance ◽  
Resistance Genes ◽  
Streptococcus Suis ◽  
Amino Acid Substitutions ◽  
Continuous Control ◽  
Antimicrobial Resistance Genes ◽  
Genes Encoding ◽  
Invasive Infections ◽  
Almost All

Streptococcus suis is a pathogen that causes invasive infections in humans and pigs. In this study, 448 S. suis isolates recovered from human infections in Thailand were characterized with regard to their antimicrobial susceptibility and antimicrobial resistance genes, including, for non-penicillin-susceptible isolates, sequence analyses of five genes encoding penicillin-binding proteins (pbp1a, pbp1b, pbp2a, pbp2b, and pbp2x). All 448 isolates were susceptible to cefepime and ceftriaxone, whereas 99.6%, 91.7%, and 72.9% of the isolates were susceptible to levofloxacin, penicillin, and chloramphenicol, respectively. Almost all isolates were resistant to tetracycline (98.2%), clindamycin (94%), erythromycin (92.4%), and azithromycin (82.6%). Genes tet(O) and ermB were the predominant resistance genes detected among macrolide- and tetracycline-resistant isolates. A total of 37 out of 448 isolates (8.2%) showed intermediately resistance to penicillin. Most of these isolates (59.5%) belonged to serotype 2-ST233. Comparison of the predicted translated sequences of five PBP proteins of a penicillin-susceptible isolate (strain P1/7) to the respective PBP sequences of ten non-penicillin-susceptible isolates revealed multiple amino acid substitutions. Isolates of CC221/234 showed highly variable amino acid substitutions in all PBP proteins. An ST104 isolate had a higher number of amino acid substitutions in PBP2X. Isolates belonging to CC233/379 had numerous substitutions in PBP2B and PBP2X. ST25 isolates exhibited fewer amino acid substitutions than isolates of other STs in all five PBPs. The antimicrobial resistance of S. suis is increasing worldwide; therefore, restrictions on antimicrobial use, continuous control, and the surveillance of this bacterium throughout the pork supply chain are crucial for ensuring public health and must be a priority concern.

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