Mitochondrial Aminoacyl-tRNA Synthetase Single-Nucleotide Polymorphisms That Lead to Defects in Refolding but Not Aminoacylation

Banerjee, Rajat; Reynolds, Noah M.; Yadavalli, Srujana S.; Rice, Cory; Roy, Hervé; Banerjee, Papri; Alexander, Rebecca W.; Ibba, Michael

doi:10.1016/j.jmb.2011.05.011

Cited by 10 publications

(8 citation statements)

References 64 publications

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“…Yet another hypothesis is that the mutations affect the partial unfolding and refolding that these proteins undergo during the import into mitochondria. Such an effect has been shown for single nucleotide polymorphisms in mitochondrial phenylalanyl-tRNA synthetase and in mitochondrial leucyl-tRNA synthetase [21].…”

Section: Discussionmentioning

confidence: 77%

Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways

Berge

Kevenaar

Polder

et al. 2013

Biochemical Journal

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The autosomal recessive white matter disorder LBSL (leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation) is caused by mutations in DARS2, coding for mtAspRS (mitochondrial aspartyl-tRNA synthetase). Generally, patients are compound heterozygous for mutations in DARS2. Many different mutations have been identified in patients, including several missense mutations. In the present study, we have examined the effects of missense mutations found in LBSL patients on the expression, enzyme activity, localization and dimerization of mtAspRS, which is important for understanding the cellular defect underlying the pathogenesis of the disease. Nine different missense mutations were analysed and were shown to have various effects on mtAspRS properties. Several mutations have a direct effect on the catalytic activity of the enzyme; others have an effect on protein expression or dimerization. Most mutations have a clear impact on at least one of the properties of mtAspRS studied, probably resulting in a small contribution of the missense variants to the mitochondrial aspartylation activity in the cell.

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Section: Discussionmentioning

confidence: 77%

Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways

Berge

Kevenaar

Polder

et al. 2013

Biochemical Journal

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“…Additional function(s) of ARS2 proteins, yet to be described, may be restricted to specific cell types or to specific developmental stages. The fact that in many mt-aaRS related disorders even severe mutations do not display an aminoacylation defect has prompted further studies which have highlighted the importance of the aminoacylation process [ 5 , 13 , 55 ], protein folding [ 56 , 57 ], and refolding [ 58 ]. Therefore the NARS2 mutations described in this study may disrupt protein refolding in the mitochondrial matrix in a tissue-specific manner.…”

Section: Discussionmentioning

confidence: 99%

Mutations of Human NARS2, Encoding the Mitochondrial Asparaginyl-tRNA Synthetase, Cause Nonsyndromic Deafness and Leigh Syndrome

et al. 2015

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Here we demonstrate association of variants in the mitochondrial asparaginyl-tRNA synthetase NARS2 with human hearing loss and Leigh syndrome. A homozygous missense mutation ([c.637G>T; p.Val213Phe]) is the underlying cause of nonsyndromic hearing loss (DFNB94) and compound heterozygous mutations ([c.969T>A; p.Tyr323*] + [c.1142A>G; p.Asn381Ser]) result in mitochondrial respiratory chain deficiency and Leigh syndrome, which is a neurodegenerative disease characterized by symmetric, bilateral lesions in the basal ganglia, thalamus, and brain stem. The severity of the genetic lesions and their effects on NARS2 protein structure cosegregate with the phenotype. A hypothetical truncated NARS2 protein, secondary to the Leigh syndrome mutation p.Tyr323* is not detectable and p.Asn381Ser further decreases NARS2 protein levels in patient fibroblasts. p.Asn381Ser also disrupts dimerization of NARS2, while the hearing loss p.Val213Phe variant has no effect on NARS2 oligomerization. Additionally we demonstrate decreased steady-state levels of mt-tRNAAsn in fibroblasts from the Leigh syndrome patients. In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2. However, overexpression of the hearing loss associated p.Val213Phe mutant protein in these fibroblasts cannot complement the OCR and ETC defects. Our findings establish lesions in NARS2 as a new cause for nonsyndromic hearing loss and Leigh syndrome.

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“…Mitochondrial proteins that are synthesized in the cytosol have to undergo either a partial or complete unfolding driven by the protein import machineries or the mitochondrial membrane potential to facilitate the transportation process across the mitochondrial membrane (28). It has previously been established that HsmitPheRS undergoes a low pH-induced partial unfolding that may actually facilitate the transport process due to the generation of a local pH gradient across the mitochondrial membrane (26). The pathogenic variants studied here were additionally found to form a molten globule-like structure at lower pH, and showed increased ANS fluorescence at lower pH compared to WT HsmitPheRS, indicating that the hydrophobic patches are much more exposed to solvents in the variants than in WT.…”

Section: Discussionmentioning

confidence: 99%

Biophysical characterization Of Alpers encephalopathy associated mutants of human mitochondrial phenylalanyl‐tRNA synthetase

2019

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Mutations in nucleus‐encoded mitochondrial aminoacyl‐tRNA synthetases (mitaaRSs) lead to defects in mitochondrial translation affecting the expression and function of 13 subunits of the respiratory chain complex leading to diverse pathological conditions. Mutations in the FARS2 gene encoding human mitochondrial phenylalanyl‐tRNA synthetase (HsmitPheRS) have been found to be associated with two different clinical representations, infantile Alpers encephalopathy and spastic paraplegia. Here we have studied three pathogenic mutants (Tyr144Cys, Ile329Thr, and Asp391Val) associated with Alpers encephalopathy to understand how these variants affect the biophysical properties of the enzyme. These mutants have already been reported to have reduced aminoacylation activity. Our study established that the mutants are significantly more thermolabile compared to the wild‐type enzyme with reduced solubility in vitro. The presence of aggregation‐prone insoluble HsmitPheRS variants could have a detrimental impact on organellar translation, and potentially impact normal mitochondrial function. © 2019 IUBMB Life, 71(8): 1141–1149, 2019 © 2019 IUBMB Life, 71(8):1141–1149, 2019

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Mitochondrial Aminoacyl-tRNA Synthetase Single-Nucleotide Polymorphisms That Lead to Defects in Refolding but Not Aminoacylation

Cited by 10 publications

References 64 publications

Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways

Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways

Mutations of Human NARS2, Encoding the Mitochondrial Asparaginyl-tRNA Synthetase, Cause Nonsyndromic Deafness and Leigh Syndrome

Biophysical characterization Of Alpers encephalopathy associated mutants of human mitochondrial phenylalanyl‐tRNA synthetase

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