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.

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 HRI coordinates translation necessary for protein homeostasis and mitochondrial function in erythropoiesis

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Shuping Zhang ◽  
Alejandra Macias-Garcia ◽  
Jacob C Ulirsch ◽  
Jason Velazquez ◽  
Vincent L Butty ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Mitochondrial Function ◽  
Ribosomal Proteins ◽  
Target Genes ◽  
Mitochondrial Protein ◽  
Erythroid Differentiation ◽  
Protein Translation ◽  
Ribosome Profiling ◽  
Underlying Mechanisms

Iron and heme play central roles in the production of red blood cells, but the underlying mechanisms remain incompletely understood. Heme-regulated eIF2α kinase (HRI) controls translation by phosphorylating eIF2α. Here, we investigate the global impact of iron, heme, and HRI on protein translation in vivo in murine primary erythroblasts using ribosome profiling. We validate the known role of HRI-mediated translational stimulation of integratedstressresponse mRNAs during iron deficiency in vivo. Moreover, we find that the translation of mRNAs encoding cytosolic and mitochondrial ribosomal proteins is substantially repressed by HRI during iron deficiency, causing a decrease in cytosolic and mitochondrial protein synthesis. The absence of HRI during iron deficiency elicits a prominent cytoplasmic unfolded protein response and impairs mitochondrial respiration. Importantly, ATF4 target genes are activated during iron deficiency to maintain mitochondrial function and to enable erythroid differentiation. We further identify GRB10 as a previously unappreciated regulator of terminal erythropoiesis.

scholarly journals Mitochondrial Plasticity Promotes Resistance to Sorafenib and Vulnerability to STAT3 Inhibition in Human Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6029
Author(s):  
Shusil K. Pandit ◽  
Giada Sandrini ◽  
Jessica Merulla ◽  
Valentina Nobili ◽  
Xin Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Ribosomal Proteins ◽  
Prolonged Exposure ◽  
Kinase Inhibitor ◽  
Mitochondrial Protein ◽  
Protein Translation ◽  
Therapeutic Benefits ◽  
Primary Treatment Modality ◽  
Hcc Cells ◽  
Resistant Cells

The multi-kinase inhibitor sorafenib is a primary treatment modality for advanced-stage hepatocellular carcinoma (HCC). However, the therapeutic benefits are short-lived due to innate and acquired resistance. Here, we examined how HCC cells respond to sorafenib and adapt to continuous and prolonged exposure to the drug. Sorafenib-adapted HCC cells show a profound reprogramming of mitochondria function and marked activation of genes required for mitochondrial protein translation and biogenesis. Mitochondrial ribosomal proteins and components of translation and import machinery are increased in sorafenib-resistant cells and sorafenib-refractory HCC patients show similar alterations. Sorafenib-adapted cells also exhibited increased serine 727 phosphorylated (pSer727) STAT3, the prevalent form in mitochondria, suggesting that STAT3 might be an actionable target to counteract resistance. Consistently, a small-molecule STAT3 inhibitor reduces pSer727, reverts mitochondrial alterations, and enhances the response to sorafenib in resistant cells. These results sustain the importance of mitochondria plasticity in response to sorafenib and identify a clinically actionable strategy for improving the treatment efficacy in HCC patients.

scholarly journals tRNA-Dependent Import of a Transit Sequence-Less Aminoacyl-tRNA Synthetase (LeuRS2) into the Mitochondria of Arabidopsis

2021 ◽  
Vol 22 (8) ◽  
pp. 3808
Author(s):  
Steffen Reinbothe ◽  
Claudia Rossig ◽  
John Gray ◽  
Sachin Rustgi ◽  
Diter von Wettstein ◽  
...  
Keyword(s):  
Protein Complex ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mitochondrial Protein ◽  
Protein Translation ◽  
Trna Synthetase ◽  
In Planta ◽  
Trna Synthetases ◽  
And Function

Aminoacyl-tRNA synthetases (AaRS) charge tRNAs with amino acids for protein translation. In plants, cytoplasmic, mitochondrial, and chloroplast AaRS exist that are all coded for by nuclear genes and must be imported from the cytosol. In addition, only a few of the mitochondrial tRNAs needed for translation are encoded in mitochondrial DNA. Despite considerable progress made over the last few years, still little is known how the bulk of cytosolic AaRS and respective tRNAs are transported into mitochondria. Here, we report the identification of a protein complex that ties AaRS and tRNA import into the mitochondria of Arabidopsis thaliana. Using leucyl-tRNA synthetase 2 (LeuRS2) as a model for a mitochondrial signal peptide (MSP)-less precursor, a ≈30 kDa protein was identified that interacts with LeuRS2 during import. The protein identified is identical with a previously characterized mitochondrial protein designated HP30-2 (encoded by At3g49560) that contains a sterile alpha motif (SAM) similar to that found in RNA binding proteins. HP30-2 is part of a larger protein complex that contains with TIM22, TIM8, TIM9 and TIM10 four previously identified components of the translocase for MSP-less precursors. Lack of HP30-2 perturbed mitochondrial biogenesis and function and caused seedling lethality during greening, suggesting an essential role of HP30-2 in planta.

scholarly journals Ribosomopathies: human disorders of ribosome dysfunction

Blood ◽  
2010 ◽  
Vol 115 (16) ◽  
pp. 3196-3205 ◽  
Author(s):  
Anupama Narla ◽  
Benjamin L. Ebert
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Macrocytic Anemia ◽  
Protein Translation ◽  
Dyskeratosis Congenita ◽  
Treacher Collins Syndrome ◽  
Diamond Blackfan Anemia ◽  
Genes Encoding ◽  
Novel Therapeutic Strategies ◽  
And Function

Abstract Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, Schwachman-Diamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q− syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases.

scholarly journals Limb Specific Failure of Proliferation and Translation in the Mesenchyme Leads to Skeletal Defects in Diamond Blackfan Anemia

2022 ◽  
Author(s):  
Jimmy Hom ◽  
Theodoros Karnavas ◽  
Emily Hartman ◽  
Julien Papoin ◽  
Yuefeng Tang ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Protein Translation ◽  
Site Specific ◽  
Diamond Blackfan Anemia ◽  
Hind Limbs ◽  
Skeletal Defects ◽  
Proliferation And Differentiation ◽  
Genes Encoding

Ribosomopathies are a class of disorders caused by defects in the structure or function of the ribosome and characterized by tissue-specific abnormalities. Diamond Blackfan anemia (DBA) arises from different mutations, predominantly in genes encoding ribosomal proteins (RPs). Apart from the anemia, skeletal defects are among the most common anomalies observed in patients with DBA, but they are virtually restricted to radial ray and other upper limb defects. What leads to these site-specific skeletal defects in DBA remains a mystery. Using a novel mouse model for RP haploinsufficiency, we observed specific, differential defects of the limbs. Using complementary in vitro and in vivo approaches, we demonstrate that reduced WNT signaling and subsequent increased β-catenin degradation in concert with increased expression of p53 contribute to mesenchymal lineage failure. We observed differential defects in the proliferation and differentiation of mesenchymal stem cells (MSCs) from the forelimb versus the hind limbs of the RP haploinsufficient mice that persisted after birth and were partially rescued by allelic reduction of Trp53. These defects are associated with a global decrease in protein translation in RP haploinsufficient MSCs, with the effect more pronounced in cells isolated from the forelimbs. Together these results demonstrate translational differences inherent to the MSC, explaining the site-specific skeletal defects observed in DBA.

scholarly journals The DYRK1A protein kinase regulates ribosome mass and translation rates through transcriptional control of ribosomal protein genes expression

2021 ◽  
Author(s):  
Chiara Di Vona ◽  
Laura Barba ◽  
Roberto Ferrari ◽  
Susana de la Luna
Keyword(s):  
Ribosomal Proteins ◽  
Transcriptional Control ◽  
Protein Translation ◽  
Ribosomal Protein Genes ◽  
Expression Of Genes ◽  
Specific Subset ◽  
Cell Proliferation And Differentiation ◽  
Dual Specificity ◽  
Global Protein Synthesis ◽  
Genes Encoding

ABSTRACTRibosomal proteins (RPs) are evolutionary conserved proteins that are essential for protein translation. RP expression must be tightly regulated, both to ensure the appropriate assembly of ribosomes and to respond to the growth demands of cells. The elements regulating the transcription of RP genes (RPGs) have been characterized in yeast and Drosophila, yet how cells regulate the production of RPs in mammals is less well understood. The dual-specificity tyrosine-regulated kinase 1A (DYRK1A) is known to participate in cell proliferation and differentiation in mammals, and its dysregulation is associated with disease in humans. Here, we show that DYRK1A marks a specific subset of proximal RPG promoters, which are characterized by the presence of the palindromic TCTCGCGAGA motif. The presence of DYRK1A at these promoters is associated with enhanced binding of the TATA-binding protein, TBP, and it is negatively correlated with the binding of the GABP transcription factor, establishing at least two clusters of RPGs that could be coordinately regulated. Indeed, DYRK1A depletion leads to a reduction of both RP mRNA and protein. Significantly, cells in which DYRK1A is depleted have fewer ribosomes, reduced global protein synthesis and they are smaller. Based on these results, we propose a novel role for DYRK1A in coordinating the expression of genes encoding RPs, thereby controlling cell growth in mammals.

scholarly journals The Leukodystrophies HBSL and LBSL—Correlates and Distinctions

2021 ◽  
Vol 14 ◽  
Author(s):  
Annapoorani Muthiah ◽  
Gary D. Housley ◽  
Matthias Klugmann ◽  
Dominik Fröhlich
Keyword(s):  
Disease Modeling ◽  
Single Gene ◽  
Mitochondrial Protein ◽  
Protein Translation ◽  
Underlying Disease ◽  
Trna Synthetases ◽  
Gene Therapies ◽  
Mouse Mutants ◽  
Magnetic Resonance Imaging Mri ◽  
Experimental Treatments

Aminoacyl-tRNA synthetases (ARSs) accurately charge tRNAs with their respective amino acids. As such, they are vital for the initiation of cytosolic and mitochondrial protein translation. These enzymes have become increasingly scrutinized in recent years for their role in neurodegenerative disorders caused by the mutations of ARS-encoding genes. This review focuses on two such genes—DARS1 and DARS2—which encode cytosolic and mitochondrial aspartyl-tRNA synthetases, and the clinical conditions associated with mutations of these genes. We also describe attempts made at modeling these conditions in mice, which have both yielded important mechanistic insights. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a disease caused by a range of mutations in the DARS2 gene, initially identified in 2003. Ten years later, hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL), caused by mutations of cytosolic DARS1, was discovered. Multiple parallels have been drawn between the two conditions. The Magnetic Resonance Imaging (MRI) patterns are strikingly similar, but still set these two conditions apart from other leukodystrophies. Clinically, both conditions are characterized by lower limb spasticity, often associated with other pyramidal signs. However, perhaps due to earlier detection, a wider range of symptoms, including peripheral neuropathy, as well as visual and hearing changes have been described in LBSL patients. Both HBSL and LBSL are spectrum disorders lacking genotype to phenotype correlation. While the fatal phenotype of Dars1 or Dars2 single gene deletion mouse mutants revealed that the two enzymes lack functional redundancy, further pursuit of disease modeling are required to shed light onto the underlying disease mechanism, and enable examination of experimental treatments, including gene therapies.

scholarly journals Reduced ribosomes of the apicoplast and mitochondrion of Plasmodium spp. and predicted interactions with antibiotics

Open Biology ◽  
2014 ◽  
Vol 4 (5) ◽  
pp. 140045 ◽  
Author(s):  
Ankit Gupta ◽  
Priyanka Shah ◽  
Afreen Haider ◽  
Kirti Gupta ◽  
Mohammad Imran Siddiqi ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Protein Translation ◽  
Small Subunit ◽  
Diatom Species ◽  
Species Comparison ◽  
Protein Subunits ◽  
Translation Factors ◽  
And Function ◽  
Unique Composition ◽  
Cross Species Comparison

Apicomplexan protists such as Plasmodium and Toxoplasma contain a mitochondrion and a relic plastid (apicoplast) that are sites of protein translation. Although there is emerging interest in the partitioning and function of translation factors that participate in apicoplast and mitochondrial peptide synthesis, the composition of organellar ribosomes remains to be elucidated. We carried out an analysis of the complement of core ribosomal protein subunits that are encoded by either the parasite organellar or nuclear genomes, accompanied by a survey of ribosome assembly factors for the apicoplast and mitochondrion. A cross-species comparison with other apicomplexan, algal and diatom species revealed compositional differences in apicomplexan organelle ribosomes and identified considerable reduction and divergence with ribosomes of bacteria or characterized organelle ribosomes from other organisms. We assembled structural models of sections of Plasmodium falciparum organellar ribosomes and predicted interactions with translation inhibitory antibiotics. Differences in predicted drug–ribosome interactions with some of the modelled structures suggested specificity of inhibition between the apicoplast and mitochondrion. Our results indicate that Plasmodium and Toxoplasma organellar ribosomes have a unique composition, resulting from the loss of several large and small subunit proteins accompanied by significant sequence and size divergences in parasite orthologues of ribosomal proteins.

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