scholarly journals Mitochondrial DNA transcription and translation: clinical syndromes

2018 ◽  
Vol 62 (3) ◽  
pp. 321-340 ◽  
Author(s):  
Veronika Boczonadi ◽  
Giulia Ricci ◽  
Rita Horvath
Keyword(s):  
Mitochondrial Protein ◽  
Clinical Manifestations ◽  
Mitochondrial Diseases ◽  
Mitochondrial Translation ◽  
Tissue Specific ◽  
Functional Studies ◽  
Whole Exome ◽  
Clinical Syndromes ◽  
Chain Defects ◽  
Nuclear Mutations

Diagnosing primary mitochondrial diseases is challenging in clinical practice. Although, defective oxidative phosphorylation (OXPHOS) is the common final pathway, it is unknown why different mtDNA or nuclear mutations result in largely heterogeneous and often tissue -specific clinical presentations. Mitochondrial tRNA (mt-tRNA) mutations are frequent causes of mitochondrial diseases both in children and adults. However numerous nuclear mutations involved in mitochondrial protein synthesis affecting ubiquitously expressed genes have been reported in association with very tissue specific clinical manifestations suggesting that there are so far unknown factors determining the tissue specificity in mitochondrial translation. Most of these gene defects result in histological abnormalities and multiple respiratory chain defects in the affected organs. The clinical phenotypes are usually early-onset, severe, and often fatal, implying the importance of mitochondrial translation from birth. However, some rare, reversible infantile mitochondrial diseases are caused by very specific defects of mitochondrial translation. An unbiased genetic approach (whole exome sequencing, RNA sequencing) combined with proteomics and functional studies revealed novel factors involved in mitochondrial translation which contribute to the clinical manifestation and recovery in these rare reversible mitochondrial conditions.

Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease

2021 ◽  
Author(s):  
Wen-Qiang Zheng ◽  
Signe Vandal Pedersen ◽  
Kyle Thompson ◽  
Emanuele Bellacchio ◽  
Courtney E French ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Clinical Phenotype ◽  
Homology Modelling ◽  
Mitochondrial Diseases ◽  
Trna Synthetase ◽  
Unrelated Patient ◽  
Mitochondrial Translation ◽  
Respiratory Chain Enzyme ◽  
Functional Studies ◽  
Pathogenic Variants

Abstract TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNAThr and clearing mischarged Ser-tRNAThr during mitochondrial translation. Pathogenic variants in TARS2 have hitherto been reported in a pair of siblings and an unrelated patient with an early onset mitochondrial encephalomyopathy and a combined respiratory chain enzyme deficiency in muscle. We here report five additional unrelated patients with TARS2-related mitochondrial diseases, expanding the clinical phenotype to also include epilepsy, dystonia, hyperhidrosis and severe hearing impairment. Additionally, we document seven novel TARS2 variants—one nonsense variant and six missense variants—that we demonstrate are pathogenic and causal of the disease presentation based on population frequency, homology modelling and functional studies that show the effects of the pathogenic variants on TARS2 stability and/or function.

scholarly journals Facial cleft? The first case of manitoba‐oculo‐tricho‐anal syndrome with novel mutations in China: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shuchen Gu ◽  
Yimin Khoong ◽  
Xin Huang ◽  
Tao Zan
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Manifestations ◽  
Sporadic Case ◽  
Facial Cleft ◽  
Ocular Manifestations ◽  
First Case ◽  
Whole Exome ◽  
Chinese Girl ◽  
Low Prevalence

Abstract Background Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare syndrome with only 27 cases reported worldwide so far, but none was reported in the population of Eastern Asia. Such extremely low prevalence might be contributed by misdiagnosis due to its similarities in ocular manifestations with facial cleft. In our study, we discovered the first case of MOTA syndrome in the population of China, with 2 novel FRAS1 related extracellular matrix 1 (FREM1) gene stop-gain mutations confirmed by whole exome sequencing. Case presentation A 12-year-old Chinese girl presented with facial cleft-like deformities including aberrant hairline, blepharon-coloboma and broad bifid nose since birth. Whole exome sequencing resulted in the identification of 2 novel stop-gain mutations in the FREM1 gene. Diagnosis of MOTA syndrome was then established. Conclusions We discovered the first sporadic case of MOTA syndrome according to clinical manifestations and genetic etiology in the Chinese population. We have identified 2 novel stop-gain mutations in FREM1 gene which further expands the spectrum of mutational seen in the MOTA syndrome. Further research should be conducted for better understanding of its mechanism, establishment of an accurate diagnosis, and eventually the exploitation of a more effective and comprehensive therapeutic intervention for MOTA syndrome.

scholarly journals The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 300
Author(s):  
Camilla Ceccatelli Berti ◽  
Giulia di Punzio ◽  
Cristina Dallabona ◽  
Enrico Baruffini ◽  
Paola Goffrini ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mitochondrial Diseases ◽  
Yeast Saccharomyces Cerevisiae ◽  
Genome Data ◽  
New Genes ◽  
Eukaryotic Organism ◽  
Novel Variants ◽  
Therapeutic Molecules ◽  
Nuclear Mutations

The increasing application of next generation sequencing approaches to the analysis of human exome and whole genome data has enabled the identification of novel variants and new genes involved in mitochondrial diseases. The ability of surviving in the absence of oxidative phosphorylation (OXPHOS) and mitochondrial genome makes the yeast Saccharomyces cerevisiae an excellent model system for investigating the role of these new variants in mitochondrial-related conditions and dissecting the molecular mechanisms associated with these diseases. The aim of this review was to highlight the main advantages offered by this model for the study of mitochondrial diseases, from the validation and characterisation of novel mutations to the dissection of the role played by genes in mitochondrial functionality and the discovery of potential therapeutic molecules. The review also provides a summary of the main contributions to the understanding of mitochondrial diseases emerged from the study of this simple eukaryotic organism.

scholarly journals Exploring the Ability of LARS2 Carboxy-Terminal Domain in Rescuing the MELAS Phenotype

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 674
Author(s):  
Francesco Capriglia ◽  
Francesca Rizzo ◽  
Giuseppe Petrosillo ◽  
Veronica Morea ◽  
Giulia d’Amati ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Molecular Mechanisms ◽  
Mitochondrial Protein ◽  
Trna Synthetase ◽  
Mitochondrial Protein Synthesis ◽  
Mitochondrial Translation ◽  
Terminal Domain ◽  
Carboxy Terminal Domain ◽  
Mitochondrial Functions ◽  
Carboxy Terminal

The m.3243A>G mutation within the mitochondrial mt-tRNALeu(UUR) gene is the most prevalent variant linked to mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome. This pathogenic mutation causes severe impairment of mitochondrial protein synthesis due to alterations of the mutated tRNA, such as reduced aminoacylation and a lack of post-transcriptional modification. In transmitochondrial cybrids, overexpression of human mitochondrial leucyl-tRNA synthetase (LARS2) has proven effective in rescuing the phenotype associated with m.3243A>G substitution. The rescuing activity resides in the carboxy-terminal domain (Cterm) of the enzyme; however, the precise molecular mechanisms underlying this process have not been fully elucidated. To deepen our knowledge on the rescuing mechanisms, we demonstrated the interactions of the Cterm with mutated mt-tRNALeu(UUR) and its precursor in MELAS cybrids. Further, the effect of Cterm expression on mitochondrial functions was evaluated. We found that Cterm ameliorates de novo mitochondrial protein synthesis, whilst it has no effect on mt-tRNALeu(UUR) steady-state levels and aminoacylation. Despite the complete recovery of cell viability and the increase in mitochondrial translation, Cterm-overexpressing cybrids were not able to recover bioenergetic competence. These data suggest that, in our MELAS cell model, the beneficial effect of Cterm may be mediated by factors that are independent of the mitochondrial bioenergetics.

scholarly journals Germline variant in REXO2 is a novel candidate gene in familial pheochromocytoma

2020 ◽  
Vol 102 ◽  
Author(s):  
Yael Laitman ◽  
Shay Tzur ◽  
Ruben Attali ◽  
Amit Tirosh ◽  
Eitan Friedman
Keyword(s):  
Allelic Imbalance ◽  
Chromosomal Region ◽  
Cancer Susceptibility ◽  
Functional Studies ◽  
Cancer Susceptibility Genes ◽  
Whole Exome ◽  
Familial Pheochromocytoma ◽  
The Family ◽  
Recombination Processes

Abstract Pheochromocytoma (PCC) is a rare, mostly benign tumour of the adrenal medulla. Hereditary PCC accounts for ~35% of cases and has been associated with germline mutations in several cancer susceptibility genes (e.g., KIF1B, SDHB, VHL, SDHD, RET). We performed whole-exome sequencing in a family with four PCC-affected patients in two consecutive generations and identified a potential novel candidate pathogenic variant in the REXO2 gene that affects splicing (c.531-1G>T (NM 015523.3)), which co-segregated with the phenotype in the family. REXO2 encodes for RNA exonuclease 2 protein and localizes to 11q23, a chromosomal region displaying allelic imbalance in PCC. REXO2 protein has been associated with DNA repair, replication and recombination processes and thus its inactivation may contribute to tumorigenesis. While the study suggests that this novel REXO2 gene variant underlies PCC in this family, additional functional studies are required in order to establish the putative role of the REXO2 gene in PCC predisposition.

scholarly journals Mitochondrial Syndromes Revisited

2021 ◽  
Vol 10 (6) ◽  
pp. 1249
Author(s):  
Daniele Orsucci ◽  
Elena Caldarazzo Ienco ◽  
Andrea Rossi ◽  
Gabriele Siciliano ◽  
Michelangelo Mancuso
Keyword(s):  
Clinical Trials ◽  
Genetic Basis ◽  
Phenotypic Variability ◽  
Mitochondrial Diseases ◽  
Genetic Alterations ◽  
Mitochondrial Disorders ◽  
Single Mutation ◽  
Multicenter Studies ◽  
Future Studies ◽  
Clinical Syndromes

In the last ten years, the knowledge of the genetic basis of mitochondrial diseases has significantly advanced. However, the vast phenotypic variability linked to mitochondrial disorders and the peculiar characteristics of their genetics make mitochondrial disorders a complex group of disorders. Although specific genetic alterations have been associated with some syndromic presentations, the genotype–phenotype relationship in mitochondrial disorders is complex (a single mutation can cause several clinical syndromes, while different genetic alterations can cause similar phenotypes). This review will revisit the most common syndromic pictures of mitochondrial disorders, from a clinical rather than a molecular perspective. We believe that the new phenotype definitions implemented by recent large multicenter studies, and revised here, may contribute to a more homogeneous patient categorization, which will be useful in future studies on natural history and clinical trials.

Stable transfer and restricted expression of a cloned class I gene encoding a secreted transplantation-like antigen

1985 ◽  
Vol 5 (6) ◽  
pp. 1295-1300
Author(s):  
Y Barra ◽  
K Tanaka ◽  
K J Isselbacher ◽  
G Khoury ◽  
G Jay
Keyword(s):  
Molecular Mechanisms ◽  
Cell Types ◽  
Class I ◽  
Regulatory Sequences ◽  
Transcriptional Enhancer ◽  
Gene Encoding ◽  
Specific Expression ◽  
Tissue Specific ◽  
Functional Studies ◽  
I Gene

The identification of a unique major histocompatibility complex class I gene, designated Q10, which encodes a secreted rather than a cell surface antigen has led to questions regarding its potential role in regulating immunological functions. Since the Q10 gene is specifically activated only in the liver, we sought to define the molecular mechanisms which control its expression in a tissue-specific fashion. Results obtained by transfection of the cloned Q10 gene, either in the absence or presence of a heterologous transcriptional enhancer, into a variety of cell types of different tissue derivations are consistent with the Q10 gene being regulated at two levels. The first is by a cis-dependent mechanism which appears to involve site-specific DNA methylation. The second is by a trans-acting mechanism which would include the possibility of an enhancer binding factor. The ability to efficiently express the Q10 gene in certain transfected cell lines offers an opportunity to obtain this secreted class I antigen in quantities sufficient for functional studies; this should also make it possible to define regulatory sequences which may be responsible for the tissue-specific expression of Q10.

Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes

1992 ◽  
Vol 12 (2) ◽  
pp. 480-490
Author(s):  
M P King ◽  
Y Koga ◽  
M Davidson ◽  
E A Schon
Keyword(s):  
Steady State ◽  
Lactic Acidosis ◽  
Respiratory Chain ◽  
Mitochondrial Myopathy ◽  
Polyacrylamide Gel Electrophoresis ◽  
Mitochondrial Protein ◽  
Morphological Characteristics ◽  
Nucleotide Position ◽  
Mitochondrial Translation ◽  
Steady State Levels

Cytoplasts from two unrelated patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) harboring an A----G transition at nucleotide position 3243 in the tRNA(Leu(UUR)) gene of the mitochondrial genome were fused with human cells lacking endogenous mitochondrial DNA (mtDNA) (rho 0 cells). Selected cybrid lines, containing less than 15 or greater than or equal to 95% mutated genomes, were examined for differences in genetic, biochemical, and morphological characteristics. Cybrids containing greater than or equal to 95% mutant mtDNA, but not those containing normal mtDNA, exhibited decreases in the rates of synthesis and in the steady-state levels of the mitochondrial translation products. In addition, NADH dehydrogenase subunit 1 (ND 1) exhibited a slightly altered mobility on polyacrylamide gel electrophoresis. The mutation also correlated with a severe respiratory chain deficiency. A small but consistent increase in the steady-state levels of an RNA transcript corresponding to 16S rRNA + tRNA(Leu(UUR)) + ND 1 genes was detected. However, there was no evidence of major errors in processing of the heavy-strand-encoded transcripts or of altered steady-state levels or ratios of mitochondrial rRNAs or mRNAs. These results provide evidence for a direct relationship between the tRNALeu(UUR) mutation and the pathogenesis of this mitochondrial disease.

scholarly journals Using mitoribosomal profiling to investigate human mitochondrial translation

2018 ◽  
Vol 2 ◽  
pp. 116
Author(s):  
Fei Gao ◽  
Maria Wesolowska ◽  
Reuven Agami ◽  
Koos Rooijers ◽  
Fabricio Loayza-Puch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Codon Position ◽  
Mitochondrial Protein ◽  
Mitochondrial Protein Synthesis ◽  
Mitochondrial Translation ◽  
Base Pairs ◽  
Suboptimal Structure ◽  
Human Counterpart ◽  
Steady State Levels

Background: Gene expression in human mitochondria has various idiosyncratic features. One of these was recently revealed as the unprecedented recruitment of a mitochondrially-encoded tRNA as a structural component of the large mitoribosomal subunit. In porcine particles this is mt-tRNAPhe whilst in humans it is mt-tRNAVal. We have previously shown that when a mutation in mt-tRNAVal causes very low steady state levels, there is preferential recruitment of mt-tRNAPhe. We have investigated whether this altered mitoribosome affects intra-organellar protein synthesis. Methods: By using mitoribosomal profiling we have revealed aspects of mitoribosome behaviour with its template mt-mRNA under both normal conditions as well as those where the mitoribosome has incorporated mt-tRNAPhe. Results: Analysis of the mitoribosome residency on transcripts under control conditions reveals that although mitochondria employ only 22 mt-tRNAs for protein synthesis, the use of non-canonical wobble base pairs at codon position 3 does not cause any measurable difference in mitoribosome occupancy irrespective of the codon. Comparison of the profile of aberrant mt-tRNAPhe containing mitoribosomes with those of controls that integrate mt-tRNAVal revealed that the impaired translation seen in the latter was not due to stalling on triplets encoding either of these amino acids. The alterations in mitoribosome interactions with start codons was not directly attributable to the either the use of non-cognate initiation codons or the presence or absence of 5’ leader sequences, except in the two bicistronic RNA units, RNA7 and RNA14 where the initiation sites are internal. Conclusions: These data report the power of mitoribosomal profiling in helping to understand the subtleties of mammalian mitochondrial protein synthesis. Analysis of profiles from the mutant mt-tRNAVal cell line suggest that despite mt-tRNAPhe being preferred in the porcine mitoribosome, its integration into the human counterpart results in a suboptimal structure that modifies its interaction with mt-mRNAs.

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.

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