Article
Biochemistry & Molecular Biology
Jessica M. Warren, Amanda K. Broz, Ana Martinez-Hottovy, Christian Elowsky, Alan C. Christensen, Daniel B. Sloan
Summary: The number of tRNAs encoded in plant mitochondrial genomes varies considerably. The loss of bacterial-like mitochondrial tRNA genes necessitates the import of nuclear-encoded counterparts with little sequence similarity. The evolution of aaRS subcellular localization in Sileneae reveals differing constraints on tRNA/aaRS interactions and alternative coevolutionary paths for maintaining organellar translation in plant cells.
MOLECULAR BIOLOGY AND EVOLUTION
(2023)
Article
Neurosciences
Ling-yue Kong, Yi-ze Wu, Run-qi Cheng, Pei-han Wang, Bi-wen Peng
Summary: Mitochondria play a vital role in cellular energy production and contain mitochondrial DNA (mt DNA) responsible for synthesizing respiratory chain components. Dysfunctions in mt DNA translation have been linked to various syndromes, but their precise mechanisms and implications remain to be determined. Mitochondrial tRNAs (mt tRNAs) encoded by mt DNA are known to contribute to mitochondrial dysfunction and are associated with a wide range of pathologies, including epilepsy. This review focuses on the function of mt tRNA and the role of mitochondrial aminoacyl-tRNA synthetase (mt aaRS) in summarizing common mt aaRS mutant genes causing epilepsy and the specific symptoms associated with these diseases.
MOLECULAR NEUROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Oliver Podmanicky, Fei Gao, Benjamin Munro, Matthew J. Jennings, Veronika Boczonadi, Denisa Hathazi, Juliane S. Mueller, Rita Horvath
Summary: This study investigates the molecular mechanisms triggered by three different mt-ARS defects caused by biallelic mutations in AARS2, EARS2, and RARS2, using an in vitro model of human neuronal cells. The findings highlight the unique compensatory mechanisms in proliferating neuronal progenitor cells, the dysregulation of neuronal differentiation and protein translation, and provide valuable insights into the tissue-specific compensatory mechanisms potentially underlying the phenotypes of patients with mt-ARS defects.
HUMAN MOLECULAR GENETICS
(2023)
Article
Biochemistry & Molecular Biology
Iliana Lopez-Soldado, Adrian Gabriel Torres, Raul Ventura, Inma Martinez-Ruiz, Angels Diaz-Ramos, Evarist Planet, Diane J. Cooper, Agnieszka Pazderska, Krzysztof Wanic, Declan O'Hanlon, Donal J. O'Gorman, Teresa Carbonell, Lluis Ribas de Pouplana, John J. Nolan, Antonio Zorzano, Maria Isabel Hernandez-Alvareza
Summary: Type 2 diabetes mellitus (T2D) is a major contributor to morbidity and mortality, affecting millions of people worldwide. In this study, alterations in the expression of mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in skeletal muscle of T2D patients were observed. The repression of mt-aaRSs expression was independent of age and could contribute to reduced protein synthesis in mitochondria. Additionally, an increased iNOS abundance in diabetic mice may inhibit the aminoacylation of mt-aaRSs, suggesting a regulatory role in diabetes.
Letter
Immunology
Yoshinao Muro, Yuta Yamashita, Haruka Koizumi, Mariko Ogawa-Momohara, Takuya Takeichi, Teruyuki Mitsuma, Masashi Akiyama
Summary: Anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies are helpful in identifying inflammatory myopathy patients. In a study with Japanese patients, autoantibodies against CysARS and ValARS were found in the serum of two dermatomyositis patients. One patient showed features of anti-synthetase syndrome, while the other did not. Further research is needed to explore the clinical differences among different anti-ARS antibodies.
AUTOIMMUNITY REVIEWS
(2022)
Review
Biochemistry & Molecular Biology
Sonia Figuccia, Andrea Degiorgi, Camilla Ceccatelli Berti, Enrico Baruffini, Cristina Dallabona, Paola Goffrini
Summary: Mitochondrial protein synthesis is essential for oxidative phosphorylation, with mutations in the translation apparatus being a major cause of mitochondrial diseases; Aminoacyl-tRNA synthetases attach specific amino acids to tRNAs and are encoded by nuclear genes, in contrast to mttRNAs encoded by mitochondrial genes; Next-generation sequencing has identified an increasing number of mtARSs variants associated with clinical heterogeneity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Endocrinology & Metabolism
Henna Tyynismaa
Summary: Mitochondrial aminoacyl-tRNA synthetases (mtARS) are enzymes essential for mitochondrial protein synthesis. Pathogenic variants in these genes can cause recessive mitochondrial diseases with a wide range of phenotypes. Understanding the tissue specificities and developing accurate disease models for treatment testing are ongoing challenges in this field. This article discusses current disease models that have improved our understanding of mtARS defects.
JOURNAL OF INHERITED METABOLIC DISEASE
(2023)
Article
Oncology
Krishnendu Khan, Valentin Gogonea, Paul L. Fox
Summary: Aminoacyl-tRNA synthetases (AARS) are important enzymes in mammalian cells that play a key role in protein translation. Recent studies have found that they exist in the cytoplasmic multi-tRNA synthetase complex (MSC) and have non-canonical functions in addition to their role in protein translation. These findings have the potential to be new therapeutic targets for cancer and other diseases.
TRANSLATIONAL ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Siqi Wu, Li Zheng, Zhoufei Hei, Jing-Bo Zhou, Guang Li, Peifeng Li, Jiayuan Wang, Hamid Ali, Xiao-Long Zhou, Jing Wang, Pengfei Fang
Summary: The structures of human Lysyl-tRNA synthetases (LysRSs) are more dynamic than those from single-celled organisms. Without the presence of MSC scaffold proteins, human LysRS can exist independently from the multi-tRNA synthetase complex (MSC). The interaction with the scaffold protein AIMP2 stabilizes the closed conformation of LysRS and protects its essential aminoacylation activity under stressed conditions. Deleting AIMP2 from human cells leads to slow cell growth in nutrient deficient mediums. These results suggest that the evolutionary emergence of the MSC in metazoan might be to protect the aminoacyl-tRNA synthetase components from being modified or recruited for use in other cellular pathways.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Review
Genetics & Heredity
Tamara L. Hendrickson, Whitney N. Wood, Udumbara M. Rathnayake
Summary: The selection of the twenty amino acids in the standard genetic code and the fixation of aminoacyl-tRNA synthetases (aaRSs) before LUCA were influenced by the chemical reactivity of amino acid side chains. Some amino acid properties delayed or prohibited the emergence of corresponding aaRSs, playing critical roles in defining the amino acids in the genetic code.
Article
Multidisciplinary Sciences
Krishnendu Khan, Briana Long, Valentin Gogonea, Gauravi M. Deshpande, Kommireddy Vasu, Paul L. Fox
Summary: Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes in the translation process that ligate amino acids to their corresponding transfer RNAs (tRNAs). In mammalian cells, these enzymes, along with AIMPs proteins, form a large multi-tRNA synthetase complex (MSC), whose assembly mechanism and function are still unclear. This study reveals the importance of cotranslational interactions, particularly involving AIMPs proteins, in the assembly process of the MSC. Interestingly, these cotranslational interactions sometimes involve more than two proteins, suggesting a diverse pathway for the ordered assembly of small subcomplexes into larger complexes.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Immunology
Angeles S. Galindo-Feria, Antonella Notarnicola, Ingrid E. Lundberg, Begum Horuluoglu
Summary: Anti-synthetase syndrome is an autoimmune disease characterized by the presence of autoantibodies targeting aminoacyl t-RNA synthetases along with various clinical features. This review summarizes the functions of aaRSs, their autoantigenic properties, and their association with ASSD.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Swadha Gupta, Jaykumar Jani, Jigneshkumar Vijayasurya, Jigneshkumar Mochi, Saba Tabasum, Akash Sabarwal, Anju Pappachan
Summary: Aminoacyl-tRNA synthetases (AaRSs) play essential roles in translating genetic information and have diverse functions in cellular activities such as transcription, apoptosis, angiogenesis, inflammation, and cancer. Their multifunctionality suggests their potential as therapeutic targets.
Article
Biochemistry & Molecular Biology
Gui-Xin Peng, Yong Zhang, Qin-Qin Wang, Qing-Run Li, Hong Xu, En-Duo Wang, Xiao-Long Zhou
Summary: The study revealed the crucial role of GTPBP3 in tRNA modification and its pathogenic mutations affecting structure, function, or localization. Additionally, a novel cytoplasm-localized isoform of hGTPBP3 was identified, suggesting potential noncanonical functions.
NUCLEIC ACIDS RESEARCH
(2021)
Review
Medicine, General & Internal
Yu Ding, Beibei Gao, Jinyu Huang
Summary: Mitochondrial tRNA mutations in cardiomyopathy are not well understood, but they may affect mitochondrial function and contribute to disease susceptibility. This review provides an overview of tRNA biology and discusses molecular mechanisms underlying mitochondrial dysfunction caused by tRNA mutations.
JOURNAL OF CLINICAL MEDICINE
(2022)
Editorial Material
Rheumatology
Pradip Dashraath, Soe-Na Choo, Harvard Lin, Hui-Lin Chin, Lin Lin Su, Mary Rauff, Mahesh Choolani
LANCET RHEUMATOLOGY
(2022)
Article
Genetics & Heredity
Ashley Moller-Hansen, Stephanie Huynh, Cornelius F. Boerkoel, Hui-Lin Chin
Summary: This study reports a rare case of cerebral cavernous malformations with lymphatic defects in addition to common symptoms, expanding the spectrum of KRIT1-related diseases to include lymphatic malformations and lymphatic endothelial dysfunction.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2022)
Article
Genetics & Heredity
Pierre K. Boerkoel, Katherine Dixon, Carrie Fitzsimons, Yaoqing Shen, Stephanie Huynh, Kamilla Schlade-Bartusiak, Luka Culibrk, Simon Chan, Cornelius F. Boerkoel, Steven J. M. Jones, Hui-Lin Chin
Summary: This study reports a newborn with syndromic degenerative anophthalmia and a complex de novo rearrangement of chromosome 13q. Long-read genome sequencing improved the resolution and clinical interpretation of the rearrangement, providing new insights into the molecular etiology of MAC.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2022)
Article
Genetics & Heredity
Hui-Lin Chin, Stephanie Huynh, Jahanshah Ashkani, Michael Castaldo, Katherine Dixon, Kathryn Selby, Yaoqing Shen, Marie Wright, Cornelius F. Boerkoel, Glenda Hendson, Steven J. M. Jones
Summary: Monoallelic pathogenic variants in BICD2 cause autosomal dominant Spinal Muscular Atrophy Lower Extremity Predominant 2A and 2B. Dysfunction of BICD2 leads to motor neuron loss. A novel de novo BICD2 variant was identified in a patient with diaphragmatic paralysis without typical muscle weakness and contractures, expanding the phenotypic spectrum of BICD2-related disease.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2022)
Article
Genetics & Heredity
Hui-Lin Chin, Susan Lin, Joshua Dalmann, Bhavi Modi, Emily Alderman, Areesha Salman, Kate L. Del Bel, Anna Lehman, Stuart E. Turvey, Cornelius F. Boerkoel
Summary: Disease-associated variants in the KIAA1109 gene are linked to Alkuraya-Kucinskas syndrome, with different types of variants causing varying degrees of severity. A study of a consanguineous family revealed abnormal splicing of KIAA1109 mRNA in peripheral blood, potentially explaining the milder phenotype.
EUROPEAN JOURNAL OF MEDICAL GENETICS
(2022)
Review
Biochemistry & Molecular Biology
Martina Magistrati, Alexandru Ionut Gilea, Camilla Ceccatelli Berti, Enrico Baruffini, Cristina Dallabona
Summary: In eukaryotes, specific nucleotide modifications of mitochondrial RNAs play critical roles in the synthesis of mitochondrial proteins and oxidative phosphorylation. Mutations in genes encoding for mt-RNAs modifying enzymes can cause modopathies. These mutations lead to the absence or decrease of specific nucleotide modifications, impairing the efficiency and accuracy of mitochondrial protein synthesis. Confirmation of their pathogenicity through a model system, such as Saccharomyces cerevisiae, is essential.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Medicine, General & Internal
Hui-Lin Chin, Denise Li Meng Goh
Summary: With the increasing popularity of genetic tests, doctors are now offering and ordering these tests for their patients. However, this process is more complex than it seems, and there are potential pitfalls that can lead to complaints and lawsuits. Clinical genetics involves more than just ordering tests, and doctors need to be aware of these pitfalls to ensure patient safety and protect their practice.
SINGAPORE MEDICAL JOURNAL
(2023)
Article
Oncology
Balakrishnan Solaimuthu, Michal Lichtenstein, Arata Hayashi, Anees Khatib, Inbar Plaschkes, Yuval Nevo, Mayur Tanna, Ophry Pines, Yoav D. Shaul
Summary: Fumarate hydratase (FH) plays a contradictory role in cell survival and tumorigenesis. Loss of FH initially inhibits cell proliferation and DNA damage repair, but over time cells overcome this loss and form stable clones. Impaired DNA damage response induces mutations in central signaling pathways, allowing cells to bypass the loss of FH and TCA cycle function.
Article
Biochemistry & Molecular Biology
Keren Friedman, Ofri Karmon, Uri Fridman, Yair Goldberg, Ophry Pines, Shay Ben-Aroya
Summary: Previous studies have shown that dysfunctional yeast proteasomes accumulate in the insoluble protein deposit (IPOD) and are prone to proteasome ubiquitination. However, our study reveals that only soluble proteasomes are targeted for autophagy, challenging the previous belief that sequestered proteasomes in IPOD are the substrates for proteaphagy. Moreover, the IPOD serves as an alternative pathway for the removal of inactive proteasomes that are not cleared by proteaphagy. This suggests that the relocalization of proteasomes to soluble aggregates is a crucial step in proteasome recycling through autophagy.
Article
Medicine, General & Internal
Julia Handra, Adrienne Elbert, Nour Gazzaz, Ashley Moller-Hansen, Stephanie Hyunh, Hyun Kyung Lee, Pierre Boerkoel, Emily Alderman, Erin Anderson, Lorne Clarke, Sara Hamilton, Ronnalea Hamman, Shevaun Hughes, Simon Ip, Sylvie Langlois, Mary Lee, Laura Li, Frannie Mackenzie, Millan S. S. Patel, Leah M. M. Prentice, Karan Sangha, Laura Sato, Kimberly Seath, Margaret Seppelt, Anne Swenerton, Lynn Warnock, Jessica L. Zambonin, Cornelius F. Boerkoel, Hui-Lin Chin, Linlea Armstrong
Summary: Genomic medicine is an emerging medical discipline that applies the principles of evolution, developmental biology, functional genomics, and structural genomics within clinical care. Enabling the integration of genomic medicine into clinical practice is crucial for achieving precision medicine. This paper provides a biological framework for diagnostic utility of genomic testing, and outlines the process of genomic medicine integration into clinical practice.
FRONTIERS IN MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Reut Hazan (Ben-Menachem), Dvora Lintzer, Tamar Ziv, Koyeli Das, Irit Rosenhek-Goldian, Ziv Porat, Hila Ben Ami Pilo, Sharon Karniely, Ann Saada, Neta Regev-Rudzki, Ophry Pines
Summary: Vesicular transport is a means of communication between cells, and this study focuses on organelle-to-organelle communication, specifically between mitochondria. The researchers discovered that functional mitochondria in yeast can release vesicles, which are about 100 nm in size and carry selective protein cargo, including ATP synthase subunits. These vesicles also contain a functional ATP synthase complex and have the ability to fuse with naive mitochondria, potentially delivering ATP and participating in organelle-to-organelle communication.
Article
Biochemistry & Molecular Biology
Alexandru Ionut Gilea, Martina Magistrati, Ilenia Notaroberto, Natascia Tiso, Cristina Dallabona, Enrico Baruffini
Summary: Most eukaryotes have a mitochondrial genome called mtDNA, which is replicated by the enzyme DNA polymerase ?, or Pol ?. In animals and fungi, Pol ? consists of a catalytic subunit encoded by MIP1. In humans, Pol ? is a heterotrimer composed of the catalytic subunit homolog to Mip1, encoded by POLG, and two accessory subunits. Over the past 25 years, more than 300 pathological mutations in POLG have been identified as the cause of POLG-related disorders, characterized by mtDNA deletions and depletion. This review focuses on the biochemical properties and mutations of yeast Mip1 and their impact on enzyme activity, mtDNA stability, and mutability. The use of yeast with Mip1 mutations equivalent to human ones is discussed for confirming pathogenicity, identifying phenotypic defects, and finding rescue mechanisms and compounds. The genetic interactions of other polymerases, such as Pol ?, Rev1, and Pol ?, in maintaining mtDNA stability and preventing point mutations, are also explored.
Review
Oncology
Hui-Lin Chin, Joyce Ching Mei Lam, Dheepa Christopher, Poon Limei Michelle, Benedict Yan Junrong
Summary: Genomic profiling for myeloid malignancies is a routine procedure that can identify gene mutations, including both somatic and germline variants. While germline variants are primarily intended for identification of somatic mutations, occasionally, clinically significant germline variants are also identified. This article discusses challenging cases where germline variants were found in genes not associated with the patient's phenotype, and the genetic counseling and management approaches in these situations.
FRONTIERS IN ONCOLOGY
(2023)
Article
Genetics & Heredity
Hui-Lin Chin, Miles C. Benton, Lin Yang, Kok Siong Poon, Karen M. L. Tan, Saumya S. Jamuar, Roger Foo, Hai Yang Law, Denise Li-Meng Goh, Samuel S. Chong, Paola Florez de Sessions
Summary: This study presents a case report of an individual with elevated HbA2 levels and no identifiable disease-associated variants in HBB gene. Through comprehensive analysis, a potential functional polymorphism associated with benign elevated HbA2 levels was identified, providing clarity for family planning for the patient and her family.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2023)
Review
Biochemistry & Molecular Biology
Martina Magistrati, Alexandru Ionut Gilea, Maria Carla Gerra, Enrico Baruffini, Cristina Dallabona
Summary: Mitochondrial diseases (MDs) are a group of pathologies characterized by defective mitochondrial function and energy production. The yeast Saccharomyces cerevisiae is an efficient model organism to study MDs and has been used successfully to validate pathogenic variants and discover potential treatment molecules. The drug drop test, coupled with a drug repurposing approach, allows for cost-effective and time-saving identification of molecules with high translational potential. The screening has been successful in various disease models, and further studies on complex organisms confirmed the effectiveness of the drugs, demonstrating the usefulness of this approach.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)