Cytoplasmic and mitochondrial protein translation in axonal and dendritic terminal arborization

2007 ◽  
Vol 10 (7) ◽  
pp. 828-837 ◽  
Author(s):  
Takahiro Chihara ◽  
David Luginbuhl ◽  
Liqun Luo
Keyword(s):  
Mitochondrial Protein ◽  
Protein Translation

Ketogenic Diet for KARS-Related Mitochondrial Dysfunction and Progressive Leukodystrophy

2021 ◽  
Author(s):  
Yuka Murofushi ◽  
Itaru Hayakawa ◽  
Yuichi Abe ◽  
Tatsuyuki Ohto ◽  
Kei Murayama ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Ketogenic Diet ◽  
Early Report ◽  
Mitochondrial Protein ◽  
Protein Translation ◽  
Trna Synthetase ◽  
Vitamin Supplementation ◽  
Low Oxygen ◽  
Disease Modifying Therapy ◽  
Disease Modifying

Abstract KARS encodes lysyl-tRNA synthetase, which is essential for protein translation. KARS mutations sometimes cause impairment of cytoplasmic and mitochondrial protein synthesis, and sometimes lead to progressive leukodystrophies with mitochondrial signature and psychomotor regression, and follow a rapid regressive course to premature death. There has been no disease-modifying therapy beyond supportive treatment. We present a 5-year-old male patient with an asymmetrical leukodystrophy who showed overt evidence of mitochondrial dysfunction, including elevation of lactate on brain MR spectroscopy and low oxygen consumption rate in fibroblasts. We diagnosed this patient's condition as KARS-related leukodystrophy with cerebral calcification, congenital deafness, and evidence of mitochondrial dysfunction. We employed a ketogenic diet as well as multiple vitamin supplementation with the intention to alleviate mitochondrial dysfunction. The patient showed alleviation of his psychomotor regression and even partial restoration of his abilities within 4 months. This is an early report of a potential disease-modifying therapy for KARS-related progressive leukodystrophy without appreciable adverse effects.

scholarly journals Toward a better understanding of folate metabolism in health and disease

2018 ◽  
Vol 216 (2) ◽  
pp. 253-266 ◽  
Author(s):  
Yuxiang Zheng ◽  
Lewis C. Cantley
Keyword(s):  
Cell Proliferation ◽  
Epigenetic Regulation ◽  
Historical Perspective ◽  
Mitochondrial Protein ◽  
Protein Translation ◽  
Folate Metabolism ◽  
Cellular Functions ◽  
Biochemical Processes ◽  
Health And Disease ◽  
Thymidine Monophosphate

Folate metabolism is crucial for many biochemical processes, including purine and thymidine monophosphate (dTMP) biosynthesis, mitochondrial protein translation, and methionine regeneration. These biochemical processes in turn support critical cellular functions such as cell proliferation, mitochondrial respiration, and epigenetic regulation. Not surprisingly, abnormal folate metabolism has been causally linked with a myriad of diseases. In this review, we provide a historical perspective, delve into folate chemistry that is often overlooked, and point out various missing links and underdeveloped areas in folate metabolism for future exploration.

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 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 Pathways of calcium regulation, electron transport, and mitochondrial protein translation are molecular signatures of susceptibility to recurrent exertional rhabdomyolysis in Thoroughbred racehorses

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0244556
Author(s):  
Kennedy Aldrich ◽  
Deborah Velez-Irizarry ◽  
Clara Fenger ◽  
Melissa Schott ◽  
Stephanie J. Valberg
Keyword(s):  
Electron Transport ◽  
Sarcoplasmic Reticulum ◽  
Protein Degradation ◽  
Plasma Membranes ◽  
Mitochondrial Protein ◽  
Protein Translation ◽  
Unknown Etiology ◽  
Exertional Rhabdomyolysis ◽  
Thoroughbred Racehorses ◽  
Shock Proteins

Recurrent exertional rhabdomyolysis (RER) is a chronic muscle disorder of unknown etiology in racehorses. A potential role of intramuscular calcium (Ca2+) dysregulation in RER has led to the use of dantrolene to prevent episodes of rhabdomyolysis. We examined differentially expressed proteins (DEP) and gene transcripts (DEG) in gluteal muscle of Thoroughbred race-trained mares after exercise among three groups of 5 horses each; 1) horses susceptible to, but not currently experiencing rhabdomyolysis, 2) healthy horses with no history of RER (control), 3) RER-susceptible horses treated with dantrolene pre-exercise (RER-D). Tandem mass tag LC/MS/MS quantitative proteomics and RNA-seq analysis (FDR <0.05) was followed by gene ontology (GO) and semantic similarity of enrichment terms. Of the 375 proteins expressed, 125 were DEP in RER-susceptible versus control, with 52 ↑DEP mainly involving Ca2+ regulation (N = 11) (e.g. RYR1, calmodulin, calsequestrin, calpain), protein degradation (N = 6), antioxidants (N = 4), plasma membranes (N = 3), glyco(geno)lysis (N = 3) and 21 DEP being blood-borne. ↓DEP (N = 73) were largely mitochondrial (N = 45) impacting the electron transport system (28), enzymes (6), heat shock proteins (4), and contractile proteins (12) including Ca2+ binding proteins. There were 812 DEG in RER-susceptible versus control involving the electron transfer system, the mitochondrial transcription/translational response and notably the pro-apoptotic Ca2+-activated mitochondrial membrane transition pore (SLC25A27, BAX, ATP5 subunits). Upregulated mitochondrial DEG frequently had downregulation of their encoded DEP with semantic similarities highlighting signaling mechanisms regulating mitochondrial protein translation. RER-susceptible horses treated with dantrolene, which slows sarcoplasmic reticulum Ca2+ release, showed no DEG compared to control horses. We conclude that RER-susceptibility is associated with alterations in proteins, genes and pathways impacting myoplasmic Ca2+ regulation, the mitochondrion and protein degradation with opposing effects on mitochondrial transcriptional/translational responses and mitochondrial protein content. RER could potentially arise from excessive sarcoplasmic reticulum Ca2+ release and subsequent mitochondrial buffering of excessive myoplasmic Ca2+.

scholarly journals RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation

2016 ◽  
Vol 126 (10) ◽  
pp. 3739-3757 ◽  
Author(s):  
Robert A. Jones ◽  
Tyler J. Robinson ◽  
Jeff C. Liu ◽  
Mariusz Shrestha ◽  
Veronique Voisin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Mitochondrial Protein ◽  
Protein Translation

scholarly journals Mice harboring a SCA28 patient mutation in AFG3L2 develop late-onset ataxia associated with enhanced mitochondrial proteotoxicity.

2018 ◽  
Author(s):  
Cecilia Mancini ◽  
Eriola Hoxha ◽  
Luisa Iommarini ◽  
Alessandro Brussino ◽  
Uwe Richter ◽  
...  
Keyword(s):  
Network Formation ◽  
De Novo ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Mitochondrial Protein ◽  
Atp Synthesis ◽  
Protein Translation ◽  
Mutant Mice ◽  
Mitochondrial Morphology ◽  
Missense Mutations

Spinocerebellar ataxia 28 is an autosomal dominant neurodegenerative disorder caused by missense mutations affecting the proteolytic domain of AFG3L2, a major component of the mitochondrial m-AAA protease. However, little is known of the underlying pathogenetic mechanisms or how to treat patients with SCA28. Currently available Afg3l2 mutant mice harbour deletions that lead to severe, early-onset neurological phenotypes that do not faithfully reproduce the late-onset and slowly progressing SCA28 phenotype. Here we describe production and detailed analysis of a new knock-in murine model harbouring an Afg3l2 allele carrying the p.Met665Arg patient-derived mutation. Heterozygous mutant mice developed normally but signs of ataxia were detectable by beam test at 18 months. Cerebellar pathology was negative; electrophysiological analysis showed increased spontaneous firing in Purkinje cells from heterozygous mutants with respect to wild-type controls, although not statistically significant. As homozygous mutants died perinatally with evidence of cardiac atrophy, for each genotype we generated mouse embryonic fibroblasts (MEFs) to investigate mitochondrial function. MEFs from mutant mice showed altered mitochondrial bioenergetics, with decreased basal oxygen consumption rate, ATP synthesis and mitochondrial membrane potential. Mitochondrial network formation and morphology was also altered, in line with greatly reduced expression of Opa1 fusogenic protein L-isoforms. The mitochondrial alterations observed in MEFs were also detected in cerebella of 18-month-old heterozygous mutants, suggesting they may be a hallmark of disease. Pharmacological inhibition of de novo mitochondrial protein translation with chloramphenicol caused reversal of mitochondrial morphology in homozygous mutant MEFs, supporting the relevance of mitochondrial proteotoxicity for SCA28 pathogenesis and therapy development.

Molecular defects in mitochondrial protein translation machinery

Mitochondrion ◽  
2015 ◽  
Vol 24 ◽  
pp. S42
Author(s):  
Jing Wang ◽  
Shujuan Pan ◽  
Jianli Li ◽  
Guoli Wang ◽  
Eric S. Schmitt ◽  
...  
Keyword(s):  
Mitochondrial Protein ◽  
Protein Translation ◽  
Translation Machinery ◽  
Molecular Defects

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 A Hypoxia Sensitive to Hypoxia Resistant Transformation in Long-Lived Germline Mutants

2021 ◽  
Author(s):  
Marc Ryan Van Gilst ◽  
C Hemphill ◽  
E Pylarinou-Sinclair ◽  
O Itani ◽  
B Scott ◽  
...  
Keyword(s):  
Protein Import ◽  
Mitochondrial Protein ◽  
Resistance Mechanism ◽  
Protein Translation ◽  
Germline Development ◽  
Mitochondrial Protein Import ◽  
C Elegans ◽  
Physiological Properties ◽  
Rnaseq Data ◽  
Somatic Tissues

Signals from the germline play a significant role in determining longevity in numerous animal models. In C. elegans , ablation of the germline leads to long life span and various other types of stress resistance. It has been reported that mutations that block oogenesis or an upstream step in germline development confer strong resistance to hypoxia. We report here that the hypoxia resistance of sterile mutants is dependent on developmental stage and age. In just a 12-hour period, sterile animals transform from hypoxia sensitive L4 larvae into highly hypoxia resistant adults. Since this transformation occurs in animals with no germline, the physiological programs that determine hypoxia sensitivity must occur independently of germline signals and instead rely on developmental signals from somatic tissues. Furthermore, we found two distinct mechanisms of hypoxia resistance in long-lived germline deficient animals. First, a DAF-16/FoxO independent mechanism that occurs in all hypoxia resistant sterile adults and, second, a DAF-16/FoxO dependent mechanism that confers an added layer of resistance, or “super-resistance”, to animals with no germline as they age past day 1 of adulthood. RNAseq data showed that nearly all genes involved in both cytosolic and mitochondrial protein translation, as well as in mitochondrial protein import, are repressed in germline deficient adults and further repressed as they age. The hypoxia super-resistance of aging germline deficient animals was suppressed by dual mutation of ncl-1 and larp-1 , two regulators of nucleolar biology and protein translation, demonstrating that the hypoxia super-resistance mechanism involves reduced protein translation. These studies provide novel insight into a profound physiological transformation that takes place in germline mutants during development, showing that some of the unique physiological properties of these long-lived animals are dependent on developmental repression of genes involved in protein translation, which operate independently of germline signals.

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