Mutations In tRNA Genes Research Articles

Mitochondrial tRNAGlu 14693A>G Mutation, an "Enhancer" to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy.

Leber's hereditary optic neuropathy (LHON), a maternally inherited ocular disease, is predominantly caused by mitochondrial DNA (mtDNA) mutations. Mitochondrial tRNA variants are hypothesized to amplify the pathogenic impact of three primary mutations. However, the exact mechanisms remained unclear. In the present study, the synergistic effect of the tRNAGlu 14693A>G and ND6 14484T>C mutations in three Chinese families affected by LHON is investigated. The m.14693A>G mutation nearly abolishes the pseudouridinylation at position 55 of tRNAGlu, leading to structural abnormalities, decreased stability, aberrant mitochondrial protein synthesis, and increased autophagy. In contrast, the ND6 14484T>C mutation predominantly impairs complex I function, resulting in heightened apoptosis and virtually no induction of mitochondrial autophagy compared to control cell lines. The presence of dual mutations in the same cell lines exhibited a coexistence of both upregulated cellular stress responses to mitochondrial damage, indicating a scenario of autophagy and mutation dysregulation within these dual-mutant cell lines. The data proposes a novel hypothesis that mitochondrial tRNA gene mutations generally lead to increased mitochondrial autophagy, while mutations in genes encoding mitochondrial proteins typically induce apoptosis, shedding light on the intricate interplay between different genetic factors in the manifestation of LHON.

Mistranslating tRNA variants have anticodon- and sex-specific impacts on Drosophila melanogaster.

Transfer RNAs (tRNAs) are vital in determining the specificity of translation. Mutations in tRNA genes can result in the misincorporation of amino acids into nascent polypeptides in a process known as mistranslation. Since mistranslation has different impacts, depending on the type of amino acid substitution, our goal here was to compare the impact of different mistranslating tRNASer variants on fly development, lifespan, and behaviour. We established two mistranslating fly lines, one with a tRNASer variant that misincorporates serine at valine codons (V→S) and the other that misincorporates serine at threonine codons (T→S). While both mistranslating tRNAs increased development time and developmental lethality, the severity of the impacts differed depending on amino acid substitution and sex. The V→S variant extended embryonic, larval, and pupal development whereas the T→S only extended larval and pupal development. Females, but not males, containing either mistranslating tRNA presented with significantly more anatomical deformities than controls. Mistranslating females also experienced extended lifespan whereas mistranslating male lifespan was unaffected. In addition, mistranslating flies from both sexes showed improved locomotion as they aged, suggesting delayed neurodegeneration. Therefore, although mistranslation causes detrimental effects, we demonstrate that mistranslation also has positive effects on complex traits such as lifespan and locomotion. This has important implications for human health given the prevalence of tRNA variants in humans.

Comparative Analysis of Tyrosine tRNA (MT-TY) Gene Mutation Related to Lung Cancer Patients from District Peshawar, Khyber-Pakhtunkhwa, Pakistan During 2020-2022

The uncontrolled growth of cells in the lungs is called lung cancer (LC). Majority of recorded LC cases is as a result of cigarette smoking. It is one of the most occurring types of cancer around the globe. Objective: To emphasizes on amplification of specific mitochondrial DNA (mtDNA) genes coding for tyrosine tRNA and to find out its association with LC patients of Peshawar. Methods: In 18 LC patients, the mitochondrially encoded tRNA tyrosine gene was studied. Samples were collected from the Institute of Radiotherapy & Nuclear Medicine (IRNUM), Peshawar, Khyber Pakhtunkhwa. The participants varied in age from 12 to 86 years. Patients had diabetes, hypertension, hepatitis C, bronchial asthma, dyspnea, hemoptysis, cardio myopathy, and stomach ulcers. DNA extraction and PCR of the tyr tRNA gene were performed. Along with gel electrophoresis. 8 samples were cleaned and sequenced. Results: The results were used for comparison with the reference DNA sequence of mitochondria i.e., revised Cambridge Reference Sequence (rCRS) Accession No 0129201. According to NCBI BLAST data, there were no variations in the nucleotide position 5826-5891 of the mitochondrially encoded tyrosine tRNA gene in LC subject. Chromatogram of tyrosine gene which was taken from UGENE software showed that there is no variation in Tyrosine gene subject sequence. Conclusions: We found no mutation in the mtDNA encoded tyr tRNA gene related to LC patient from District Peshawar Khyber-Pakhtunkhwa, Pakistan during 2020-2022.

The sequence variation of mitochondrial tRNA tyrosine and cysteine among Iranian women with idiopathic recurrent miscarriage: A case-control study.

Recurrent miscarriage is one of the most prevalent reproductive diseases. This phenomenon has several reasons, including maternal, hormonal, immunological, and parental genetic factors. Idiopathic recurrent miscarriage (IRM), with no distinctive etiology, involves about half of the recurrent miscarriage cases. Some mutations in mitochondrial DNA can lead to miscarriage. Mitochondrial tRNA (mt-tRNA) mutations cause nearly half of the mitochondrial disorders. To identify mt- tRNA gene mutations in Iranian women with IRM. In this case-control study, 100 Iranian women with IRM and 100 women as control without any history of miscarriage were investigated by polymerase chain reaction-single strand conformation polymorphism technique followed by gene sequencing. Bioinformatics analysis were done using human mitochondrial genome database, molecular evolutionary genetics analysis, mammalian mitochondrial-tRNA, etc. Results showed 4 mt-tRNA mutations including 1 cysteine mt-tRNA mutation (5824CT) and 3 tyrosine mt-tRNA mutations (5868TA, 5849CT, and 5836TC) in our cases. Amongst the 4 mutations found, one was novel that is still not reported. Our bioinformatics analysis revealed that these mutations can be pathogenic. They occurred in tRNA-conserved regions and their secondary structure was changed, which can result in mitochondrial dysfunction. Mutations of these genes may help in the assessment of IRM. Further study of all 22 mt-tRNAs possible mutations is recommended to describe their etiologic role in IRM.

Restoration of mitochondrial function through activation of hypomodified tRNAs with pathogenic mutations associated with mitochondrial diseases.

Mutations in mitochondrial (mt-)tRNAs frequently cause mitochondrial dysfunction. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonus epilepsy associated with ragged red fibers (MERRF) are major clinical subgroups of mitochondrial diseases caused by pathogenic point mutations in tRNA genes encoded in mtDNA. We previously reported a severe reduction in the frequency of 5-taurinomethyluridine (τm5U) and its 2-thiouridine derivative (τm5s2U) in the anticodons of mutant mt-tRNAs isolated from the cells of patients with MELAS and MERRF, respectively. The hypomodified tRNAs fail to decode cognate codons efficiently, resulting in defective translation of respiratory chain proteins in mitochondria. To restore the mitochondrial activity of MELAS patient cells, we overexpressed MTO1, a τm5U-modifying enzyme, in patient-derived myoblasts. We used a newly developed primer extension method and showed that MTO1 overexpression almost completely restored the τm5U modification of the MELAS mutant mt-tRNALeu(UUR). An increase in mitochondrial protein synthesis and oxygen consumption rate suggested that the mitochondrial function of MELAS patient cells can be activated by restoring the τm5U of the mutant tRNA. In addition, we confirmed that MTO1 expression restored the τm5s2U of the mutant mt-tRNALys in MERRF patient cells. These findings pave the way for epitranscriptomic therapies for mitochondrial diseases.

Modeling mitochondrial DNA diseases: from base editing to pluripotent stem-cell-derived organoids.

Mitochondrial DNA (mtDNA) diseases are multi-systemic disorders caused by mutations affecting a fraction or the entirety of mtDNA copies. Currently, there are no approved therapies for the majority of mtDNA diseases. Challenges associated with engineering mtDNA have in fact hindered the study of mtDNA defects. Despite these difficulties, it has been possible to develop valuable cellular and animal models of mtDNA diseases. Here, we describe recent advances in base editing of mtDNA and the generation of three-dimensional organoids from patient-derived human-induced pluripotent stem cells (iPSCs). Together with already available modeling tools, the combination of these novel technologies could allow determining the impact of specific mtDNA mutations in distinct human cell types and might help uncover how mtDNA mutation load segregates during tissue organization. iPSC-derived organoids could also represent a platform for the identification of treatment strategies and for probing the in vitro effectiveness of mtDNA gene therapies. These studies have the potential to increase our mechanistic understanding of mtDNA diseases and may open the way to highly needed and personalized therapeutic interventions.

Genomic Changes and Genetic Divergence of Vibrio alginolyticus Under Phage Infection Stress Revealed by Whole-Genome Sequencing and Resequencing.

Bacteriophages (phages) and their bacterial hosts were the most abundant and genetically highly diverse organisms on the earth. In this study, a series of phage-resistant mutant (PRM) strains derived from Vibrio alginolyticus were isolated and Infrequent-restriction-site PCR (IRS-PCR) was used to investigate the genetic diversity of the PRM strains. Phenotypic variations of eight PRM strains were analyzed using profiles of utilizing carbon sources and chemical sensitivity. Genetic variations of eight PRM strains and coevolved V. alginolyticus populations with phages were analyzed by whole-genome sequencing and resequencing, respectively. The results indicated that eight genetically discrepant PRM stains exhibited abundant and abundant phenotypic variations. Eight PRM strains and coevolved V. alginolyticus populations (VE1, VE2, and VE3) contained numerous single nucleotide variations (SNVs) and insertions/indels (InDels) and exhibited obvious genetic divergence. Most of the SNVs and InDels in coding genes were related to the synthesis of flagellar, extracellular polysaccharide (EPS), which often served as the receptors of phage invasion. The PRM strains and the coevolved cell populations also contained frequent mutations in tRNA and rRNA genes. Two out of three coevolved populations (VE1 and VE2) contained a large mutation segment severely deconstructing gene nrdA, which was predictably responsible for the booming of mutation rate in the genome. In summary, numerous mutations and genetic divergence were detected in the genomes of V. alginolyticus PRM strains and in coevolved cell populations of V. alginolyticus under phage infection stress. The phage infection stress may provide an important force driving genomic evolution of V. alginolyticus.

Mitochondrial tRNA Mutation and Regulation of the Adiponectin Pathway in Maternally Inherited Hypertension in Chinese Han.

Some essential hypertension (EH) patients show maternal inheritance, which is the mode of mitochondrial DNA inheritance. This study examines the mechanisms by which mitochondrial mutations cause EH characterized by maternal inheritance. The study enrolled 115 volunteers, who were divided into maternally inherited EH (group A, n = 17), non-maternally inherited EH (group B, n = 65), and normal control (group C, n = 33) groups. A mitochondrial tRNA (15910 C>T) gene mutation was significantly correlated with EH and may play an important role in the pathogenesis of maternally inherited EH. Examining two families carrying the mitochondrial tRNA 15910 C>T mutation, which disrupted base pairing and may affect the stability and function of mitochondrial tRNAThr, we find that the overall incidence of EH was 59.3% in the maternal family members and 90% in males, significantly higher than in the general population in China (23.2%), and that the EH began at a younger age in those carrying mitochondrial tRNA 15910 C>T. To reveal the mechanism through which mitochondrial tRNA 15910 C>T causes maternally inherited EH, we cultured human peripheral blood mononuclear cells from family A2 in vitro. We find that cells carrying mitochondrial tRNA 15910 C>T were more viable and proliferative, and the increased ATP production resulted in raised intracellular reactive oxygen species (ROS). Moreover, the mitochondrial dysfunction resulted in reduced APN levels, causing hypoadiponectinemia, which promoted cell proliferation, and produced more ROS. This vicious cycle promoted the occurrence of EH with maternally inherited mitochondrial tRNA 15910 C>T. The mitochondrial tRNA 15910 C>T mutation may induce hypertension by changing the APN, AdipoR1, PGC-1α, and ERRα signaling pathways to elevate blood pressure. We discover a new mitochondrial mutation (tRNA 15910 C>T) related to EH, reveal part of the mechanism by which mitochondrial mutations lead to the occurrence and development of maternally inherited EH, and discuss the role of APN in it.

MELAS-associated m.5541C>T mutation caused instability of mitochondrial tRNATrp and remarkable mitochondrial dysfunction

BackgroundMitochondrial encephalomyopathy with lactic acidosis and stroke-like episode (MELAS) is a group of genetic diseases caused by mutations in mitochondrial DNA and nuclear DNA. The causative mutations of MELAS have...

Expanding and validating the biomarkers for mitochondrial diseases

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.

Genome-wide mapping of regions preferentially targeted by the human DNA-cytosine deaminase APOBEC3A using uracil-DNA pulldown and sequencing

Activation-induced deaminase (AID) and apolipoprotein B mRNA-editing enzyme catalytic subunit (APOBEC) enzymes convert cytosines to uracils, creating signature mutations that have been used to predict sites targeted by these enzymes. Mutation-based targeting maps are distorted by the error-prone or error-free repair of these uracils and by selection pressures. To directly map uracils created by AID/APOBEC enzymes, here we used uracil-DNA glycosylase and an alkoxyamine to covalently tag and sequence uracil-containing DNA fragments (UPD-Seq). We applied this technique to the genome of repair-defective, APOBEC3A-expressing bacterial cells and created a uracilation genome map, i.e. uracilome. The peak uracilated regions were in the 5'-ends of genes and operons mainly containing tRNA genes and a few protein-coding genes. We validated these findings through deep sequencing of pulldown regions and whole-genome sequencing of independent clones. The peaks were not correlated with high transcription rates or stable RNA:DNA hybrid formation. We defined the uracilation index (UI) as the frequency of occurrence of TT in UPD-Seq reads at different original TC dinucleotides. Genome-wide UI calculation confirmed that APOBEC3A modifies cytosines in the lagging-strand template during replication and in short hairpin loops. APOBEC3A's preference for tRNA genes was observed previously in yeast, and an analysis of human tumor sequences revealed that in tumors with a high percentage of APOBEC3 signature mutations, the frequency of tRNA gene mutations was much higher than in the rest of the genome. These results identify multiple causes underlying selection of cytosines by APOBEC3A for deamination, and demonstrate the utility of UPD-Seq.

Mutations in Mitochondrial DNA From Pancreatic Ductal Adenocarcinomas Associate With Survival Times of Patients and Accumulate as Tumors Progress

Somatic mutations have been found in the mitochondria in different types of cancer cells, but it is not clear whether these affect tumorigenesis or tumor progression. We analyzed mitochondrial genomes of 268 early-stage, resected pancreatic ductal adenocarcinoma tissues and paired non-tumor tissues. We defined a mitochondrial somatic mutation (mtSNV) as a position where the difference in heteroplasmy fraction between tumor and normal sample was ≥0.2. Our analysis identified 304 mtSNVs, with at least 1 mtSNV in 61% (164 of 268) of tumor samples. The noncoding control region had the greatest proportion of mtSNVs (60 of 304 mutations); this region contains sites that regulate mitochondrial DNA transcription and replication. Frequently mutated genes included ND5, RNR2, and CO1, plus 29 mutations in transfer RNA genes. mtSNVs in 2 separate mitochondrial genes (ND4 and ND6) were associated with shorter overall survival time. This association appeared to depend on the level of mtSNV heteroplasmy. Non-random co-occurrence between mtSNVs and mutations in nuclear genes indicates interactions between nuclear and mitochondrial DNA. In an analysis of primary tumors and metastases from 6 patients, we found tumors to accumulate mitochondrial mutational mutations as they progress.

Novel and heteroplasmic mutations in mitochondrial tRNA genes in Brugada syndrome.

Brugada syndrome (BrS) is a rare cardiac arrhythmia characterized by sudden death associated with electrocardiogram patterns characterized by incomplete right bundle-branch block and ST-segment elevations in the anterior precordial leads. This syndrome predominantly is seen in younger males with structurally normal hearts. Mitochondrial variants particularly mt-tRNA mutations, are hot spots that lead to cardiological disorders. Previous studies have shown that mutations in mitochondrial tRNA genes play an important causal or modifying role in BrS. The present study aims to evaluate the involvement of mitochondrial tRNA genes in arrhythmogenic BrS. In this study, 40 Iranian patients were investigated for the presence of the mutations in 6 mitochondrial tRNA genes (tRNA Ile, Met, Gln, Asn, Ala and Trp) by PCR-SSCP analysis. There were 4 mutations in tRNA genes, that for first time, were found in BrS patients and these mutations were not in controls. Three of them were heteroplasmic and located in tRNAGln (T4377A) and tRNAMet (G4407A and C4456T) which were assessed as pathogenic mutations. A homo-plasmic variant (5580T > C) in tRNATrp gene was located within the junction region between tRNATrp and tRNAAla genes. This mutation may disturb the processing of mt-tRNATrp. The results of this study suggest that mutations in mitochondrial tRNA genes might lead to deficiencies in translational process of critical proteins of the respiratory chain and potentially lead to BrS in Iranian subjects. (Cardiol J 2018; 25, 1: 113-119).

APOBEC3B cytidine deaminase targets the non-transcribed strand of tRNA genes in yeast

Variations in mutation rates across the genome have been demonstrated both in model organisms and in cancers. This phenomenon is largely driven by the damage specificity of diverse mutagens and the differences in DNA repair efficiency in given genomic contexts. Here, we demonstrate that the single-strand DNA-specific cytidine deaminase APOBEC3B (A3B) damages tRNA genes at a 1000-fold higher efficiency than other non-tRNA genomic regions in budding yeast. We found that A3B-induced lesions in tRNA genes were predominantly located on the non-transcribed strand, while no transcriptional strand bias was observed in protein coding genes. Furthermore, tRNA gene mutations were exacerbated in cells where RNaseH expression was completely abolished (Δrnh1Δrnh35). These data suggest a transcription-dependent mechanism for A3B-induced tRNA gene hypermutation.Interestingly, in strains proficient in DNA repair, only 1% of the abasic sites formed upon excision of A3B-deaminated cytosines were not repaired leading to mutations in tRNA genes, while 18% of these lesions failed to be repaired in the remainder of the genome. A3B-induced mutagenesis in tRNA genes was found to be efficiently suppressed by the redundant activities of both base excision repair (BER) and the error-free DNA damage bypass pathway. On the other hand, deficiencies in BER did not have a profound effect on A3B-induced mutations in CAN1, the reporter for protein coding genes. We hypothesize that differences in the mechanisms underlying ssDNA formation at tRNA genes and other genomic loci are the key determinants of the choice of the repair pathways and consequently the efficiency of DNA damage repair in these regions.Overall, our results indicate that tRNA genes are highly susceptible to ssDNA-specific DNA damaging agents. However, increased DNA repair efficacy in tRNA genes can prevent their hypermutation and maintain both genome and proteome homeostasis.

Mitochondrial diseases: Yeast as a model for the study of suppressors

Mitochondrial (mt) tRNA gene mutations are an important cause of human morbidity and are associated with different syndromes. We have previously shown that the mitochondrial protein synthesis elongation factor EF-Tu and isolated sequences from the carboxy-terminal domain of yeast and human mt leucyl-tRNA synthetases (LeuRS), have a wide range of suppression capability among different yeast mt tRNA mutants having defective respiratory phenotype. Here we show that the rescuing capability can be restricted to a specific sequence of six amino acids from the carboxy-terminal domain of mt LeuRS. On the other hand by overexpressing a mutated version of mt EF-Tu in a yeast strain deleted for the endogenous nuclear gene we identified the specific region involved in suppression.Results support the possibility that a small peptide could correct defects associated with many mt tRNA mutations, suggesting a novel therapy for mitochondrial diseases treatment.The involvement of the mt EF-Tu in cellular heat stress response has also been suggested.

Pathogenic mtDNA mutations causing mitochondrial myopathy: The need for muscle biopsy

Pathogenic mitochondrial tRNA (mt-tRNA) gene mutations represent a prominent cause of primary mitochondrial DNA (mtDNA)-related disease despite accounting for only 5%-10% of the mitochondrial genome.(1,2) Although some common mt-tRNA mutations, such as the m.3243A>G mutation, exist, the majority are rare and have been reported in only a small number of cases.(3) The MT-TP gene, encoding mt-tRNA(Pro), is one of the less polymorphic mt-tRNA genes, and only 5 MT-TP mutations have been reported as a cause of mitochondrial muscle disease to date (table e-1 at Neurology.org/ng, P6-10). We report 5 patients with myopathic phenotypes, each harboring different pathogenic mutations in the MT-TP gene, highlighting the importance of MT-TP mutations as a cause of mitochondrial muscle disease and the requirement to study clinically relevant tissue.

Mitochondrial DNA triplication and punctual mutations in patients with mitochondrial neuromuscular disorders

Mitochondrial diseases are a heterogeneous group of disorders caused by the impairment of the mitochondrial oxidative phosphorylation system which have been associated with various mutations of the mitochondrial DNA (mtDNA) and nuclear gene mutations. The clinical phenotypes are very diverse and the spectrum is still expanding. As brain and muscle are highly dependent on OXPHOS, consequently, neurological disorders and myopathy are common features of mtDNA mutations. Mutations in mtDNA can be classified into three categories: large-scale rearrangements, point mutations in tRNA or rRNA genes and point mutations in protein coding genes. In the present report, we screened mitochondrial genes of complex I, III, IV and V in 2 patients with mitochondrial neuromuscular disorders. The results showed the presence the pathogenic heteroplasmic m.9157G>A variation (A211T) in the MT-ATP6 gene in the first patient. We also reported the first case of triplication of 9 bp in the mitochondrial NC7 region in Africa and Tunisia, in association with the novel m.14924T>C in the MT-CYB gene in the second patient with mitochondrial neuromuscular disorder.

MitoTALEN: A General Approach to Reduce Mutant mtDNA Loads and Restore Oxidative Phosphorylation Function in Mitochondrial Diseases.

We have designed mitochondrially targeted transcription activator-like effector nucleases or mitoTALENs to cleave specific sequences in the mitochondrial DNA (mtDNA) with the goal of eliminating mtDNA carrying pathogenic point mutations. To test the generality of the approach, we designed mitoTALENs to target two relatively common pathogenic mtDNA point mutations associated with mitochondrial diseases: the m.8344A>G tRNA(Lys) gene mutation associated with myoclonic epilepsy with ragged red fibers (MERRF) and the m.13513G>A ND5 mutation associated with MELAS/Leigh syndrome. Transmitochondrial cybrid cells harbouring the respective heteroplasmic mtDNA mutations were transfected with the respective mitoTALEN and analyzed after different time periods. MitoTALENs efficiently reduced the levels of the targeted pathogenic mtDNAs in the respective cell lines. Functional assays showed that cells with heteroplasmic mutant mtDNA were able to recover respiratory capacity and oxidative phosphorylation enzymes activity after transfection with the mitoTALEN. To improve the design in the context of the low complexity of mtDNA, we designed shorter versions of the mitoTALEN specific for the MERRF m.8344A>G mutation. These shorter mitoTALENs also eliminated the mutant mtDNA. These reductions in size will improve our ability to package these large sequences into viral vectors, bringing the use of these genetic tools closer to clinical trials.

Mitochondria: a pathogenic paradigm in hypertensive renal disease.

Mitochondria were first described in 1840 as bioblasts, elementary organisms responsible for vital cellular functions, but were subsequently named mitochondria, from the Greek names mitos (thread) and chondros (granule), which describes their appearance during spermatogenesis.1 Their discovery generated substantial interest given their structure resembling bacteria, which led in subsequent years to important scientific discoveries positioning mitochondria as the energy powerhouse of the cell. The unique architecture of mitochondria, consisting of 2 membranes (outer and inner) and compartments (intermembrane space and matrix), is crucial for their vital functions. Mitochondria serve not only as primary sources of cellular energy, but also modulate several cellular processes, including oxidative phosphorylation, calcium homeostasis, thermogenesis, oxygen sensing, proliferation, and apoptosis.2 Therefore, mitochondrial injury and dysfunction might be implicated in the pathogenesis of several diseases. Hypertension accounts for nearly 30% of patients reaching end-stage renal disease.3 Renal injury secondary to hypertension or to ischemia associated with renovascular hypertension (distal to renal artery stenosis) may have significant and detrimental effect on health outcomes. Studies have highlighted several deleterious pathways, including inflammation, oxidative stress, and fibrosis that are activated in the hypertensive kidney, eliciting functional decline.4,5 However, the precise molecular mechanisms responsible for renal injury have not been fully elucidated. Over the past few years, increasing evidence has established the experimental foundations linking mitochondrial alterations to hypertensive renal injury (Table). Mitochondriopathies, abnormalities of energy metabolism secondary to sporadic or inherited mutations in nuclear or mitochondrial DNA (mtDNA) genes, may contribute to the development and progression of hypertension and its complications. In addition, several studies have reported mitochondrial damage and dysfunction consequent to hypertensive renal disease. View this table: Table. Evidence of Renal Mitochondrial Damage in Models of Hypertension and Antihypertensive Treatment Importantly, hypertensive-induced renal injury is characterized by activation of several deleterious pathways, including oxidative stress, renin–angiotensin–aldosterone …

Welcome to the new tRNA world!

Transfer RNAs (tRNAs) are one of the classical non-coding RNAs, with lengths of approximately 70–100 bases. The secondary structure of tRNAs can be represented as a cloverleaf with four stems, and the three-dimensional structure as an “L” shape. Historically, the basic function of the tRNAs as essential components of translation was established in the 1960s, when it was found that each tRNA is charged with a target amino acid by a specific aminoacyl-tRNA synthetase, and delivers it to the ribosome during protein synthesis (Crick, 1966; Normanly and Abelson, 1989; Frank, 2000). However, recent studies suggest that the roles of tRNA in cellular regulation go beyond this paradigm. Now, tRNA is recognized as a regulator of many biological processes, and several unique tRNA genes have been discovered. Our understanding of the enzymes involved in tRNA functions has also increased and many tRNA-related diseases have been reported. In response to these exciting data, I have edited this special issue of tRNA, which revisits and summarizes the molecular biology of tRNA. The topics contributed by specialists in the field cover a wide range of tRNA research. In the last decade, a number of reports have described novel aspects of tRNAs in terms of the diversity of their genes. For example, several types of disrupted tRNA genes have been reported in the Archaea and primitive Eukarya. These include multiple-intron-containing tRNA genes, split tRNA genes, and permuted tRNA genes (Fujishima and Kanai, 2014; Soma, 2014). Because these tRNAs are encoded as precursor forms (pre-tRNAs) in the genome, they must be processed to yield mature functional tRNAs. Studies of tRNA introns and their processing enzymes suggest that rather complex pathways are required to generate mature tRNAs (Yoshihisa, 2014). Metazoan mitochondrial tRNA is another example of a unique tRNA, lacking either one or two arms of the typical tRNA cloverleaf structure (Watanabe et al., 2014), and transfer messenger RNA (tmRNA) is involved in trans-translation, the major ribosome rescue system in bacterial cells (Himeno et al., 2014). Most of these tRNA genes and a huge number of tRNA sequences from metagenomic analyses are registered on the tRNA gene databases (Abe et al., 2014). The universal 3′-terminal CCA sequence of the tRNAs, which is required for amino acid attachment to the molecule, is synthesized by tRNA nucleotidyltransferase or the “CCA-adding enzyme.” The molecular mechanism of the template-independent RNA polymerization catalyzed by the CCA-adding enzyme is discussed, based on its structural features (Tomita and Yamashita, 2014). It is well-known that tRNAs contain many types of base modifications. Recent progress in our understanding of two major modifications in tRNAs, methylated nucleosides (Hori, 2014) and thionucleosides (Shigi, 2014), is reviewed and summarized. As well as the canonical role of tRNA during protein biosynthesis, recent studies have shown that tRNA performs additional functions in regulating biochemical processes (Raina and Ibba, 2014). For example, aminoacyl-tRNA is involved in cell wall formation, protein labeling for degradation, and antibiotic biosynthesis. Moreover, tRNA cleavage is a conserved part of the responses of eukaryotic cells to various stresses. Age-associated and tissue-specific tRNA fragmentation have also been observed and several studies have suggested that some of these tRNA fragments are involved in the cellular RNA interference (RNAi) system. Pathological mutations in tRNA genes and tRNA-related enzymes have been linked to human diseases (Abbott et al., 2014). Mutations in the mitochondrial tRNA genes, in particular, are responsible for many diseases, and aminoacyl-tRNA synthetase mutations are associated with neurological diseases. Finally, the evolution of the tRNA molecule is discussed based on the analysis of the tRNA structure (Caetano-Anolles and Sun, 2014) and ancestral ribozymes (Fujishima and Kanai, 2014). Please enjoy reading all these articles, which will open the door to a new tRNA world!