Disease models of mitochondrial aminoacyl-tRNA synthetase defects

Article Cell Biology

Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy

Nicole M. Sayles et al.

Summary: Mitochondrial cardiomyopathies are fatal diseases with no effective treatment. This study reveals cardiac metabolic rewiring triggered by CHCHD10 gene mutation and the associated mechanisms of metabolic imbalance.

CELL REPORTS (2022)

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Article Biochemistry & Molecular Biology

Selective degradation of tRNASer(AGY) is the primary driver for mitochondrial seryl-tRNA synthetase-related disease

Tingting Yu et al.

Summary: Mitochondrial translation is crucial for cellular energy homeostasis, and variations in mitochondrial aaRSs can lead to various human diseases. This study identified two novel variants of SARS2 that cause a multisystem disorder. These variants exhibited reduced tRNA binding and aminoacylation capacities, resulting in mitochondrial dysfunction and decreased tRNA abundance due to RNA degradation. The findings highlight the importance of reduced tRNA(Ser)(AGY) abundance in the development of SARS2-related diseases.

NUCLEIC ACIDS RESEARCH (2022)

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Article Biochemistry & Molecular Biology

RNA granule-clustered mitochondrial aminoacyl-tRNA synthetases form multiple complexes with the potential to fine-tune tRNA aminoacylation

Gui-Xin Peng et al.

Summary: The study found that mitochondrial aminoacyl-tRNA synthetases (mito aaRSs) partially colocalize with mitochondrial RNA granules (MRGs), possibly facilitated by their tRNA-binding capacity. Additionally, several mito aaRS-containing complexes were discovered, and their activities were influenced by interactions. These findings deepen our understanding of the functional and regulatory mechanisms of mito aaRSs.

NUCLEIC ACIDS RESEARCH (2022)

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Article Biochemistry & Molecular Biology

VARS2 Depletion Leads to Activation of the Integrated Stress Response and Disruptions in Mitochondrial Fatty Acid Oxidation

Elham Kayvanpour et al.

Summary: Through experiments on zebrafish embryos and HEK293A cells, it was found that VARS2 depletion may lead to heart failure, CNS dysfunction, and skeletal muscle damage. VARS2-depleted cells showed reduced enzymatic activity, rearrangement of ETC complexes, activation of the ISR, and disruptions in mitochondrial FAO.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

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Review Genetics & Heredity

The Role of Nuclear-Encoded Mitochondrial tRNA Charging Enzymes in Human Inherited Disease

Christina Del Greco et al.

Summary: Aminoacyl-tRNA synthetases are essential enzymes involved in protein synthesis and mutations in these genes can cause a range of clinical phenotypes. Although there is significant clinical heterogeneity, the underlying mechanisms are not fully understood.

GENES (2022)

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Article Cell Biology

OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy

Sofia Ahola et al.

Summary: This study reveals that deficiencies in the oxidative phosphorylation system can lead to cardiomyopathy and heart failure in mitochondrial disease. The loss of the assembly factor Cox10 causes mitochondrial cardiomyopathy in mice, resulting in abnormalities in mitochondrial morphology and lysosomal function. The activation of the mitochondrial peptidase Oma1 triggers the integrated stress response, which has a protective role in mitochondrial cardiomyopathy. Inhibition of the integrated stress response impairs cardiac glutathione metabolism and increases lipid peroxidation, ultimately leading to ferroptosis.

CELL METABOLISM (2022)

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Review Physiology

Aminoacyl-tRNA synthetases in human health and disease

Alexandra K. Turvey et al.

Summary: Aminoacyl-tRNA synthetases (aaRSs) are enzymes that play a crucial role in protein synthesis by linking tRNA molecules with their corresponding amino acids. In addition to their canonical function, aaRSs have various non-canonical functions. The human genome contains 37 genes encoding unique aaRS proteins, and damaging variants in these genes have been linked to 56 genetic diseases. Furthermore, anti-synthetase syndrome is a rare autoimmune inflammatory myopathy caused by autoantibodies that disrupt aaRS proteins.

FRONTIERS IN PHYSIOLOGY (2022)

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Article Clinical Neurology

CLPP deficiency ameliorates neurodegeneration caused by impaired mitochondrial protein synthesis

Anastasia Rumyantseva et al.

Summary: Mitochondria are essential organelles responsible for converting food into energy in eukaryotic cells. However, our understanding of mitochondrial gene expression mechanisms and associated pathologies remains limited, with therapeutic interventions largely unexplored. Recent research suggests that targeting the mitochondrial matrix protease CLPP could improve phenotypes of mitochondrial encephalopathies by delaying neurodegeneration and improving motor functions.

BRAIN (2022)

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Article Cardiac & Cardiovascular Systems

Developmental Angiogenesis Requires the Mitochondrial Phenylalanyl-tRNA Synthetase

Bowen Li et al.

Summary: The study shows that deficiency of FARS2 can impede embryonic development and vasculature formation in zebrafish, as well as reduce cell motility and tube formation capacity in human umbilical vein endothelial cells, disrupting regulatory pathways of angiogenesis.

FRONTIERS IN CARDIOVASCULAR MEDICINE (2021)

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Article Biochemistry & Molecular Biology

Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation

Sung-Hoon Kim et al.

Summary: This study reveals a new pathway for activating mTORC1 in response to variations in threonine levels through mitochondrial synthetase TARS2. The interaction between TARS2 and Rags increases GTP loading of RagA, influencing the activity of mTORC1.

MOLECULAR CELL (2021)

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Review Neurosciences

The Leukodystrophies HBSL and LBSL-Correlates and Distinctions

Annapoorani Muthiah et al.

Summary: Aminoacyl-tRNA synthetases play a vital role in protein translation initiation, and mutations in ARS-encoding genes have been linked to neurodegenerative disorders. This review focuses on DARS1 and DARS2 genes, highlighting their involvement in leukoencephalopathy and hypomyelination disorders. While the clinical manifestations differ slightly, both conditions lack genotype to phenotype correlation and require further disease modeling for mechanistic insights and potential treatments.

FRONTIERS IN CELLULAR NEUROSCIENCE (2021)

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Article Biochemistry & Molecular Biology

An animal model for mitochondrial tyrosyl-tRNA synthetase deficiency reveals links between oxidative phosphorylation and retinal function

Xiaofen Jin et al.

Summary: YARS2 deficiency can lead to impaired mitochondrial protein synthesis, affecting the stability and activity of the oxidative phosphorylation system, ultimately causing vision impairments. Utilizing CRISPR/Cas9 technology, YARS2 knockout was successfully generated in HeLa cells and zebrafish, revealing the underlying pathophysiology and highlighting the critical role of YARS2 in mitochondrial function and vision disorders.

JOURNAL OF BIOLOGICAL CHEMISTRY (2021)

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Article Biochemistry & Molecular Biology

FARS2 deficiency in Drosophila reveals the developmental delay and seizure manifested by aberrant mitochondrial tRNA metabolism

Wenlu Fan et al.

Summary: Mutations in genes encoding mitochondrial aminoacyl-tRNA synthetases are associated with various diseases, but the precise mechanisms remain unclear. Using a Drosophila model, researchers found that inactivation of dFARS2 leads to developmental delay and seizure, and modeling human disease-associated FARS2 variants in Drosophila demonstrated their role in inducing neurological disorders. This study highlights the importance of mitochondrial aminoacylation system dysfunction in pathologies and the potential of Drosophila model for functional analysis of human disease-causing variants.

NUCLEIC ACIDS RESEARCH (2021)

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Article Neurosciences

Disruption of Hars2 in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice

Pengcheng Xu et al.

Summary: Mutations in genes encoding mitochondrial aminoacyl-tRNA synthetases can lead to sensorineural hearing loss in humans. In a mouse model with targeted knockout of histidyl-tRNA synthetase HARS2, progressive hearing loss was observed along with hair cell apoptosis and mitochondrial dysfunction. While inner hair cells demonstrated more prominent mitochondrial abnormalities, outer hair cells experienced more severe cell loss.

FRONTIERS IN CELLULAR NEUROSCIENCE (2021)

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Review Biochemistry & Molecular Biology

Mitochondrial Aminoacyl-tRNA Synthetase and Disease: The Yeast Contribution for Functional Analysis of Novel Variants

Sonia Figuccia et al.

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)

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Article Neurosciences

Neuronal ablation of mt-AspRS in mice induces immune pathway activation prior to severe and progressive cortical and behavioral disruption

Christina L. Nemeth et al.

EXPERIMENTAL NEUROLOGY (2020)

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Article Biochemistry & Molecular Biology

DARS2 is indispensable for Purkinje cell survival and protects against cerebellar ataxia

Anastasia Rumyantseva et al.

HUMAN MOLECULAR GENETICS (2020)

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Article Biochemistry & Molecular Biology

The G3-U70-independent tRNA recognition by human mitochondrial alanyl-tRNA synthetase

Qi-Yu Zeng et al.

NUCLEIC ACIDS RESEARCH (2019)

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Article Biochemistry & Molecular Biology

Instability of the mitochondrial alanyl-tRNA synthetase underlies fatal infantile-onset cardiomyopathy

Ewen W. Sommerville et al.

HUMAN MOLECULAR GENETICS (2019)

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Review Biochemistry & Molecular Biology

When a common biological role does not imply common disease outcomes: Disparate pathology linked to human mitochondrial aminoacyl-tRNA synthetases

Ligia Elena Gonzalez-Serrano et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2019)

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Article Biochemistry & Molecular Biology

Editing activity for eliminating mischarged tRNAs is essential in mammalian mitochondria

Taru Hilander et al.

NUCLEIC ACIDS RESEARCH (2018)

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Article Biochemistry & Molecular Biology

Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons

Veronika Boczonadi et al.

HUMAN MOLECULAR GENETICS (2018)

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Article Biochemistry & Molecular Biology

Three human aminoacyl-tRNA synthetases have distinct sub-mitochondrial localizations that are unaffected by disease-associated mutations

Ligia Elena Gonzalez-Serrano et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2018)

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Article Cell Biology

A Wars2 Mutant Mouse Model Displays OXPHOS Deficiencies and Activation of Tissue-Specific Stress Response Pathways

Thomas Agnew et al.

CELL REPORTS (2018)

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Article Biochemistry & Molecular Biology

DARS2 protects against neuroinflammation and apoptotic neuronal loss, but is dispensable for myelin producing cells

Marijana Aradjanski et al.

HUMAN MOLECULAR GENETICS (2017)

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Review Biochemistry & Molecular Biology

Recent Advances in Mitochondrial Aminoacyl-tRNA Synthetases and Disease

Marie Sissler et al.

TRENDS IN MOLECULAR MEDICINE (2017)

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Article Cell Biology

Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools and Remodel One-Carbon Metabolism

Joni Nikkanen et al.

CELL METABOLISM (2016)

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Article Biochemistry & Molecular Biology

Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt

Dominic Seiferling et al.

EMBO REPORTS (2016)

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Article Genetics & Heredity

Splicing Defect in Mitochondrial Seryl-tRNA Synthetase Gene Causes Progressive Spastic Paresis Instead of HUPRA Syndrome

Tarja Linnankivi et al.

HUMAN MUTATION (2016)

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Article Biochemistry & Molecular Biology

A Human Disease-causing Point Mutation in Mitochondrial Threonyl-tRNA Synthetase Induces Both Structural and Functional Defects

Yong Wang et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2016)

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Article Multidisciplinary Sciences

Wars2 is a determinant of angiogenesis

Mao Wang et al.

NATURE COMMUNICATIONS (2016)

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Article Biology

Mitochondrial dysfunction remodels one - carbon metabolism in human cells

Xiaoyan Robert Bao et al.

ELIFE (2016)

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Article Genetics & Heredity

Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation

Liliya Euro et al.

FRONTIERS IN GENETICS (2015)

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Article Clinical Neurology

DARS-associated leukoencephalopathy can mimic a steroid-responsive neuroinflammatory disorder

Nicole I. Wolf et al.

NEUROLOGY (2015)

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Article Cell Biology

Tissue-Specific Loss of DARS2 Activates Stress Responses Independently of Respiratory Chain Deficiency in the Heart

Sukru Anil Dogan et al.

CELL METABOLISM (2014)

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Article Clinical Neurology

Novel (ovario) leukodystrophy related to AARS2 mutations

Cristina Dallabona et al.

NEUROLOGY (2014)

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Article Genetics & Heredity

Mutations in DARS Cause Hypomyelination with Brain Stem and Spinal Cord Involvement and Leg Spasticity

Ryan J. Taft et al.

AMERICAN JOURNAL OF HUMAN GENETICS (2013)

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Review Endocrinology & Metabolism

Mitochondrial aminoacyl-tRNA synthetases in human disease

Svetlana Konovalova et al.

MOLECULAR GENETICS AND METABOLISM (2013)

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Article Biochemistry & Molecular Biology

Human mitochondrial disease-like symptoms caused by a reduced tRNA aminoacylation activity in flies

Tanit Guitart et al.

NUCLEIC ACIDS RESEARCH (2013)

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Review Biochemistry & Molecular Biology

Mitochondria: In Sickness and in Health

Jodi Nunnari et al.

CELL (2012)

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Article Biochemistry & Molecular Biology

Mutations in the Mitochondrial Methionyl-tRNA Synthetase Cause a Neurodegenerative Phenotype in Flies and a Recessive Ataxia (ARSAL) in Humans

Vafa Bayat et al.

PLOS BIOLOGY (2012)

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Article Genetics & Heredity

Mutations in the Mitochondrial Seryl-tRNA Synthetase Cause Hyperuricemia, Pulmonary Hypertension, Renal Failure in Infancy and Alkalosis, HUPRA Syndrome

Ruth Belostotsky et al.

AMERICAN JOURNAL OF HUMAN GENETICS (2011)

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Article Genetics & Heredity

Exome Sequencing Identifies Mitochondrial Alanyl-tRNA Synthetase Mutations in Infantile Mitochondrial Cardiomyopathy

Alexandra Gotz et al.

AMERICAN JOURNAL OF HUMAN GENETICS (2011)

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Article Biochemistry & Molecular Biology

Impairment of the tRNA-splicing endonuclease subunit 54 (tsen54) gene causes neurological abnormalities and larval death in zebrafish models of pontocerebellar hypoplasia

Paul R. Kasher et al.

HUMAN MOLECULAR GENETICS (2011)

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Article Biochemistry & Molecular Biology

Mitochondrial myopathy induces a starvation-like response

Henna Tyynismaa et al.

HUMAN MOLECULAR GENETICS (2010)

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Review Biochemistry & Molecular Biology

Mouse models of mitochondrial DNA defects and their relevance for human disease

Henna Tyynismaa et al.

EMBO REPORTS (2009)

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Article Genetics & Heredity

Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation

Gert C. Scheper et al.

NATURE GENETICS (2007)

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Disease models of mitochondrial aminoacyl-tRNA synthetase defects

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