Posttranscriptional modifications in mitochondrial tRNA and its implication in mitochondrial translation and disease

2020 ◽  
Vol 168 (5) ◽  
pp. 435-444
Author(s):  
Tomizawa Kazuhito ◽  
Fan-Yan Wei
Keyword(s):  
Mitochondrial Diseases ◽  
Protein Translation ◽  
Fundamental Aspect ◽  
Trna Genes ◽  
Mitochondrial Translation ◽  
Mitochondrial Trna ◽  
Genes Encoding ◽  
Stability Structure ◽  
Life Threatening ◽  
Mrna Binding

Abstract A fundamental aspect of mitochondria is that they possess DNA and protein translation machinery. Mitochondrial DNA encodes 22 tRNAs that translate mitochondrial mRNAs to 13 polypeptides of respiratory complexes. Various chemical modifications have been identified in mitochondrial tRNAs via complex enzymatic processes. A growing body of evidence has demonstrated that these modifications are essential for translation by regulating tRNA stability, structure and mRNA binding, and can be dynamically regulated by the metabolic environment. Importantly, the hypomodification of mitochondrial tRNA due to pathogenic mutations in mitochondrial tRNA genes or nuclear genes encoding modifying enzymes can result in life-threatening mitochondrial diseases in humans. Thus, the mitochondrial tRNA modification is a fundamental mechanism underlying the tight regulation of mitochondrial translation and is essential for life. In this review, we focus on recent findings on the physiological roles of 5-taurinomethyl modification (herein referred as taurine modification) in mitochondrial tRNAs. We summarize the findings in human patients and animal models with a deficiency of taurine modifications and provide pathogenic links to mitochondrial diseases. We anticipate that this review will help understand the complexity of mitochondrial biology and disease.

scholarly journals Mitochondrial Protein Translation: Emerging Roles and Clinical Significance in Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Fei Wang ◽  
Deyu Zhang ◽  
Dejiu Zhang ◽  
Peifeng Li ◽  
Yanyan Gao
Keyword(s):  
Ribosomal Proteins ◽  
Large Fraction ◽  
Mitochondrial Protein ◽  
Mitochondrial Diseases ◽  
Protein Translation ◽  
Genetic System ◽  
Mitochondrial Rna ◽  
Trna Synthetases ◽  
Translation Factors ◽  
Genes Encoding

Mitochondria are one of the most important organelles in cells. Mitochondria are semi-autonomous organelles with their own genetic system, and can independently replicate, transcribe, and translate mitochondrial DNA. Translation initiation, elongation, termination, and recycling of the ribosome are four stages in the process of mitochondrial protein translation. In this process, mitochondrial protein translation factors and translation activators, mitochondrial RNA, and other regulatory factors regulate mitochondrial protein translation. Mitochondrial protein translation abnormalities are associated with a variety of diseases, including cancer, cardiovascular diseases, and nervous system diseases. Mutation or deletion of various mitochondrial protein translation factors and translation activators leads to abnormal mitochondrial protein translation. Mitochondrial tRNAs and mitochondrial ribosomal proteins are essential players during translation and mutations in genes encoding them represent a large fraction of mitochondrial diseases. Moreover, there is crosstalk between mitochondrial protein translation and cytoplasmic translation, and the imbalance between mitochondrial protein translation and cytoplasmic translation can affect some physiological and pathological processes. This review summarizes the regulation of mitochondrial protein translation factors, mitochondrial ribosomal proteins, mitochondrial tRNAs, and mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in the mitochondrial protein translation process and its relationship with diseases. The regulation of mitochondrial protein translation and cytoplasmic translation in multiple diseases is also summarized.

scholarly journals Mutational Screening for Mitochondrial tRNA Mutations in 150 Children with High Myopia

2021 ◽  
Vol 31 (5) ◽  
Author(s):  
Tian Xia ◽  
Ying Pang ◽  
Huimin Xiong
Keyword(s):  
Mitochondrial Dysfunction ◽  
High Myopia ◽  
Phenotypic Expression ◽  
Active Role ◽  
Unknown Etiology ◽  
Trna Genes ◽  
Mitochondrial Translation ◽  
Mitochondrial Trna ◽  
Pathogenic Variants ◽  
Mutational Screening

Background: Myopia is a very common eye disease with an unknown etiology. Increasing evidence shows that mitochondrial dysfunction plays an active role in the pathogenesis and progression of this disease. Objectives: The purpose of this study was to analyze the relationship between mitochondrial tRNA (mt-tRNA) variants and high myopia (HM). Methods: The entire mt-tRNA genes of 150 children with HM, as well as 100 healthy subjects, were PCR-amplified and sequenced. To assess the pathogenicity, we used the phylogenetic conservation analysis and pathogenicity scoring system. Results: We identified six candidate pathogenic variants: tRNALeu (UUR) T3290C, tRNAIle A4317G, tRNAAla G5591A, tRNASer (UCN) T7501C, tRNAHis T12201C, and tRNAThr G15915A. However, these variants were not identified in controls. Further phylogenetic analysis revealed that these variants occurred at the positions, which were very evolutionarily conserved and may have structural-functional impacts on the tRNAs. Subsequently, these variants may lead to the impairment of mitochondrial translation and aggravated mitochondrial dysfunction, which play an active role in the phenotypic expression of HM. Conclusions: Our results suggested that variants in mt-tRNA genes were the risk factors for HM, which provided valuable information for the early detection and prevention of HM.

scholarly journals Expanding and validating the biomarkers for mitochondrial diseases

2020 ◽  
Vol 98 (10) ◽  
pp. 1467-1478
Author(s):  
Alessandra Maresca ◽  
◽  
Valentina Del Dotto ◽  
Martina Romagnoli ◽  
Chiara La Morgia ◽  
...  
Keyword(s):  
Metabolic Disorders ◽  
Nuclear Genome ◽  
Mitochondrial Diseases ◽  
Genetic Alterations ◽  
Fibroblast Growth Factor 21 ◽  
Trna Genes ◽  
The Novel ◽  
Longitudinal Assessment ◽  
Mitochondrial Translation ◽  
Monitoring Therapy

Abstract Mitochondrial diseases are highly heterogeneous metabolic disorders caused by genetic alterations in the mitochondrial DNA (mtDNA) or in the nuclear genome. In this study, we investigated a panel of blood biomarkers in a cohort of 123 mitochondrial patients, with prominent neurological and muscular manifestations. These biomarkers included creatine, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF-15), and the novel cell free circulating-mtDNA (ccf-mtDNA). All biomarkers were significantly increased in the patient group. After stratification by the specific phenotypes, ccf-mtDNA was significantly increased in the Mitochondrial Encephalomyopathy Lactic Acidosis Stroke-like episodes syndrome (MELAS) group, and FGF21 and GDF-15 were significantly elevated in patients with MELAS and Myoclonic Epilepsy Ragged Red Fibers syndrome. On the contrary, in our cohort, creatine was not associated to a specific clinical phenotype. Longitudinal assessment in four MELAS patients showed increased levels of ccf-mtDNA in relation to acute events (stroke-like episodes/status epilepticus) or progression of neurodegeneration. Our results confirm the association of FGF21 and GDF-15 with mitochondrial translation defects due to tRNA mutations. Most notably, the novel ccf-mtDNA was strongly associated with MELAS and may be used for monitoring the disease course or to evaluate the efficacy of therapies, especially in the acute phase. Key messages • FGF21/GDF15 efficiently identifies mitochondrial diseases due to mutations in tRNA genes. • The novel ccf-mtDNA is associated with MELAS and increases during acute events. • Creatine only discriminates severe mitochondrial patients. • FGF21, GDF-15, and ccf-mtDNA are possibly useful for monitoring therapy efficacy.

scholarly journals Clinical and diagnostic features of infantile liver failure caused by TRMU gene mutations

2020 ◽  
pp. 95-96
Author(s):  
Н.А. Семенова ◽  
П.Г. Цыганкова ◽  
Е.Л. Дадали ◽  
Т.В. Строкова ◽  
Н.Н. Таран ◽  
...  
Keyword(s):  
Liver Failure ◽  
Mitochondrial Disorder ◽  
Gene Mutations ◽  
Spontaneous Remission ◽  
Mitochondrial Translation ◽  
Mitochondrial Trna ◽  
Gene Encoding ◽  
Diagnostic Features ◽  
Life Threatening ◽  
Prompt Diagnosis

Мутации в гене TRMU, кодирующем одну из митохондриальных тРНК метилтрансфераз, были обнаружены при инфантильной гепатопатии, связанной с дефектом митохондриальной трансляции (OMIM#613070). Это заболевание является редким заболеванием с угрожающим жизни началом и во многих случаях с последующей спонтанной ремиссией. Своевременная диагностика и лечение таких больных имеют важное значение в клинической практике. В статье приводится описание пациента с печеночной недостаточностью, обусловленной мутациями в гене TRMU, и сравнение клинической картины с литературными данными. Mutations in the TRMU gene encoding the mitochondrial tRNA-specific 2-thiouridylase were found in infantile hepatopathy related to mitochondrial translation defect (OMIM# 613070). This condition is rare mitochondrial disorder with a life-threatening onset and with spontaneous remission, therefore a prompt diagnosis and treatment of these patients has importance in clinical practice. Here we describe a patient, with liver failure due to mutations in TRMU gene and compare with patients from literature.

scholarly journals Mitochondrial tRNA import – the challenge to understand has just begun

2009 ◽  
Vol 390 (8) ◽  
Author(s):  
Juan D. Alfonzo ◽  
Dieter Söll
Keyword(s):  
Oxidative Phosphorylation ◽  
Mitochondrial Genomes ◽  
Trna Genes ◽  
Mitochondrial Membranes ◽  
Mitochondrial Translation ◽  
Mitochondrial Trna ◽  
Trna Import ◽  
Made In ◽  
In Cells

Abstract Mitochondrial translation is important for the synthesis of proteins involved in oxidative phosphorylation, which yields the bulk of the ATP made in cells. During evolution most mitochondria-containing organisms have lost tRNA genes from their mitochondrial genomes. Thus, to support the essential process of nuanced mitochondrial translation, mechanisms to actively transport tRNAs from the cytoplasm across the mitochondrial membranes into the mitochondrion have evolved. Here, we review the currently known tRNA import mechanisms, comment on recent discoveries of various import factors, and suggest a rationale for forces that lie behind the evolution of mitochondrial tRNA import.

scholarly journals The Early Transcriptional Response of Human Granulocytes to Infection with Candida albicans Is Not Essential for Killing but Reflects Cellular Communications

2006 ◽  
Vol 75 (3) ◽  
pp. 1493-1501 ◽  
Author(s):  
Chantal Fradin ◽  
Abigail L. Mavor ◽  
Günther Weindl ◽  
Martin Schaller ◽  
Karin Hanke ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mononuclear Cells ◽  
De Novo ◽  
Transcriptional Response ◽  
Mononuclear Leukocytes ◽  
General Notion ◽  
Genes Encoding ◽  
Global Transcriptional Profile ◽  
Life Threatening ◽  
Systemic Infections

ABSTRACT Candida albicans is a polymorphic opportunistic fungus that can cause life-threatening systemic infections following hematogenous dissemination in patients susceptible to nosocomial infection. Neutrophils form part of the innate immune response, which is the first line of defense against microbes and is particularly important in C. albicans infections. To compare the transcriptional response of leukocytes exposed to C. albicans, we investigated the expression of key cytokine genes in polymorphonuclear and mononuclear leukocytes after incubation with C. albicans for 1 h. Isolated mononuclear cells expressed high levels of genes encoding proinflammatory signaling molecules, whereas neutrophils exhibited much lower levels, similar to those observed in whole blood. The global transcriptional profile of neutrophils was examined by using an immunology-biased human microarray to determine whether different morphological forms or the viability of C. albicans altered the transcriptome. Hyphal cells appeared to have the broadest effect, although the most strongly induced genes were regulated independently of morphology or viability. These genes were involved in proinflammatory cell-cell signaling, cell signal transduction, and cell growth. Generally, genes encoding known components of neutrophil granules showed no upregulation at this time point; however, lactoferrin, a well-known candidacidal peptide, was secreted by neutrophils. Addition to inhibitors of RNA or protein de novo synthesis did not influence the killing activity within 30 min. These results support the general notion that neutrophils do not require gene transcription to mount an immediate and direct attack against microbes. However, neutrophils exposed to C. albicans express genes involved in communication with other immune cells.

scholarly journals Three mitochondrial tRNA genes fromArabidopsis thaliana: evidence for the conversion of a tRNAPhegene into a tRNATyrgene

1989 ◽  
Vol 17 (7) ◽  
pp. 2613-2622 ◽  
Author(s):  
Hsu-Ching Chen ◽  
Henri Wintz ◽  
Jacques-Henry Weil ◽  
Datta T.N. Pillay
Keyword(s):  
Trna Genes ◽  
Mitochondrial Trna ◽  
Mitochondrial Trna Genes

scholarly journals In Vitro Import of a Nuclearly Encoded tRNA into Mitochondria of Solanum tuberosum

2003 ◽  
Vol 23 (11) ◽  
pp. 4000-4012 ◽  
Author(s):  
Ludovic Delage ◽  
André Dietrich ◽  
Anne Cosset ◽  
Laurence Maréchal-Drouard
Keyword(s):  
Solanum Tuberosum ◽  
Higher Plants ◽  
Plant Mitochondria ◽  
Protein Translation ◽  
Trna Genes ◽  
Vitro Assay ◽  
Trna Import

ABSTRACT Some of the mitochondrial tRNAs of higher plants are nuclearly encoded and imported into mitochondria. The import of tRNAs encoded in the nucleus has been shown to be essential for proper protein translation within mitochondria of a variety of organisms. Here, we report the development of an in vitro assay for import of nuclearly encoded tRNAs into plant mitochondria. This in vitro system utilizes isolated mitochondria from Solanum tuberosum and synthetic tRNAs transcribed from cloned nuclear tRNA genes. Although incubation of radioactively labeled in vitro-transcribed tRNAAla, tRNAPhe, and tRNAMet-e with isolated potato mitochondria resulted in importation, as measured by nuclease protection, the amount of tRNA transcripts protected at saturation was at least five times higher for tRNAAla than for the two other tRNAs. This difference in in vitro saturation levels of import is consistent with the in vivo localization of these tRNAs, since cytosolic tRNAAla is naturally imported into potato mitochondria whereas tRNAPhe and tRNAMet-e are not. Characterization of in vitro tRNA import requirements indicates that mitochondrial tRNA import proceeds in the absence of any added cytosolic protein fraction, involves at least one protein component on the surface of mitochondria, and requires ATP-dependent step(s) and a membrane potential.

Characterization of mutant mitochondrial plasmids of Neurospora spp. that have incorporated tRNAs by reverse transcription

1989 ◽  
Vol 9 (2) ◽  
pp. 678-691
Author(s):  
R A Akins ◽  
R L Kelley ◽  
A M Lambowitz
Keyword(s):  
Mitochondrial Dna ◽  
Reverse Transcription ◽  
Transcription Initiation ◽  
Consensus Sequence ◽  
Trna Genes ◽  
Wild Type ◽  
Mitochondrial Trna ◽  
Mitochondrial Plasmids ◽  
Circular Dnas ◽  
Mitochondrial Introns

The Mauriceville and Varkud mitochondrial plasmids of Neurospora spp. are closely related, closed-circular DNAs (3.6 and 3.7 kilobases, respectively) whose nucleotide sequences and genetic organization suggest relationships to mitochondrial introns and retroelements. We have characterized nine suppressive mutants of these plasmids that outcompete mitochondrial DNA and lead to impaired growth. All nine suppressive plasmids contain small insertions, corresponding to or including a mitochondrial tRNA (tRNATrp, tRNAGly, or tRNAVal) or a tRNA-like sequence. The insertions are located at the position corresponding to the 5' end of the major plasmid transcript or 24 nucleotides downstream near a cognate of the sequence at the major 5' RNA end. The structure of the suppressive plasmids suggests that the tRNAs were inserted via an RNA intermediate. The 3' end of the wild-type plasmid transcript can itself be folded into a secondary structure which has tRNA-like characteristics, similar to the tRNA-like structures at the 3' ends of plant viral RNAs. This structure may play a role in replication of the plasmids by reverse transcription. Major transcripts of the suppressive plasmids begin at the 5' end of the inserted mitochondrial tRNA sequence and are present in 25- to 100-fold-higher concentrations than are transcripts of wild-type plasmids. Mapping of 5' RNA ends within the inserted mtDNA sequences identifies a short consensus sequence (PuNPuAG) which is present at the 5' ends of a subset of mitochondrial tRNA genes. This sequence, together with sequences immediately upstream in the plasmids, forms a longer consensus sequence, which is similar to sequences at transcription initiation sites in Neurospora mitochondrial DNA. The suppressive behavior of the plasmids is likely to be directly related to the insertion of tRNAs leading to overproduction of plasmid transcripts.

scholarly journals Premature ovarian insufficiency may be associated with the mutations in mitochondrial tRNA genes

2019 ◽  
Vol 66 (1) ◽  
pp. 81-88 ◽  
Author(s):  
Yu Ding ◽  
Bo-Hou Xia ◽  
Guang-Chao Zhuo ◽  
Cai-Juan Zhang ◽  
Jian-Hang Leng
Keyword(s):  
Premature Ovarian Insufficiency ◽  
Trna Genes ◽  
Mitochondrial Trna ◽  
Ovarian Insufficiency ◽  
Mitochondrial Trna Genes
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