Mitochondrial tRNA Mutations: Clinical and Functional Perturbations

Zifa, Emily; Giannouli, Stamatina; Theotokis, Paschalis; Stamatis, Costas; Mamuris, Zissis; Stathopoulos, Constantinos

doi:10.4161/rna.4.1.4548

Cited by 52 publications

(50 citation statements)

References 282 publications

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“…[26][27][28] Most mutations are transitions (pyrimidine into pyrimidine and/or purine into purine), rather than conversions, and are localized throughout the acceptor stem and the anticodon arm of the tRNA body. Kinetic experiments showed a reduced aminoacylation activity of hmPheRS toward the mutated tRNA Phe variants.…”

Section: Acceptor Stem Recognitionmentioning

confidence: 99%

Crystal Structure of Human Mitochondrial PheRS Complexed with tRNAPhe in the Active “Open” State

Klipcan

Moor

Finarov

et al. 2012

Journal of Molecular Biology

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Section: Acceptor Stem Recognitionmentioning

confidence: 99%

Crystal Structure of Human Mitochondrial PheRS Complexed with tRNAPhe in the Active “Open” State

Klipcan

Moor

Finarov

et al. 2012

Journal of Molecular Biology

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“…More than half of pathogenic mtDNA mutations are located in genes controlling tRNA expression 41. Such mutations lead to reduced tRNA steady‐state levels, decreased mitochondrial protein synthesis, and destabilized tRNA secondary or tertiary structure42, 43 and impaired oxidative phosphorylation and oxygen consumption 43.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA Sequence Variants Associated With Blood Pressure Among 2 Cohorts of Older Adults

Buford

Manini

Kairalla

et al. 2018

JAHA

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BackgroundAge‐related changes in blood pressure are associated with a variety of poor health outcomes. Genetic factors are proposed contributors to age‐related increases in blood pressure, but few genetic loci have been identified. We examined the role of mitochondrial genomic variation in blood pressure by sequencing the mitochondrial genome.Methods and ResultsMitochondrial DNA (mtDNA) data from 1755 participants from the LIFE (Lifestyle Interventions and Independence for Elders) studies and 788 participants from the Health ABC (Health, Aging, and Body Composition) study were evaluated using replication analysis followed by meta‐analysis. Participants were aged ≥69 years, of diverse racial backgrounds, and assessed for systolic blood pressure (SBP), diastolic blood pressure, and mean arterial pressure. After meta‐analysis across the LIFE and Health ABC studies, statistically significant associations of mtDNA variants with higher SBP (m.3197T>C, 16S rRNA; P=0.0005) and mean arterial pressure (m.15924A>G, t‐RNA‐thr; P=0.004) were identified in white participants. Among black participants, statistically significant associations with higher SBP (m.93A>G, HVII; m.16183A>C, HVI; both P=0.0001) and mean arterial pressure (m.16172T>C, HVI; m.16183A>C, HVI; m.16189T>C, HVI; m.12705C>T; all P's<0.0004) were observed. Significant pooled effects on SBP were observed across all transfer RNA regions (P=0.0056) in white participants. The individual and aggregate variant results are statistically significant after multiple comparisons adjustment for the number of mtDNA variants and mitochondrial regions examined.ConclusionsThese results suggest that mtDNA‐encoded variants are associated with variation in SBP and mean arterial pressure among older adults. These results may help identify mitochondrial activities to explain differences in blood pressure in older adults and generate new hypotheses surrounding mtDNA variation and the regulation of blood pressure.Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT01072500 and NCT00116194.

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“…More than 130 pathogenic mutations (see MITOMAP available online) have been observed in mitochondrial tRNA genes (48). Numerous studies have been carried out in efforts to delin- eate the underlying causes for the defects observed in genetic diseases arising from mutations in mitochondrial tRNA genes (43).…”

Section: Discussionmentioning

confidence: 99%

A Disease-causing Point Mutation in Human Mitochondrial tRNAMet Results in tRNA Misfolding Leading to Defects in Translational Initiation and Elongation

Jones

Graham

et al. 2008

Journal of Biological Chemistry

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The mitochondrial tRNA genes are hot spots for mutations that lead to human disease. A single point mutation (T4409C) in the gene for human mitochondrial tRNA Met (hmtRNA Met ) has been found to cause mitochondrial myopathy. This mutation results in the replacement of U8 in hmtRNA Met with a C8. The hmtRNA Met serves both in translational initiation and elongation in human mitochondria making this tRNA of particular interest in mitochondrial protein synthesis. Here we show that the single 8U3 C mutation leads to a failure of the tRNA to respond conformationally to Mg 2؉ . This mutation results in a drastic disruption of the structure of the hmtRNA Met , which significantly reduces its aminoacylation. The small fraction of hmtRNA Met that can be aminoacylated is not formylated by the mitochondrial Met-tRNA transformylase preventing its function in initiation, and it is unable to form a stable ternary complex with elongation factor EF-Tu preventing any participation in chain elongation. We have used structural probing and molecular reconstitution experiments to examine the structures formed by the normal and mutated tRNAs. In the presence of Mg 2؉ , the normal tRNA displays the structural features expected of a tRNA. However, even in the presence of Mg 2؉ , the mutated tRNA does not form the cloverleaf structure typical of tRNAs. Thus, we believe that this mutation has disrupted a critical Mg 2؉ -binding site on the tRNA required for formation of the biologically active structure. This work establishes a foundation for understanding the physiological consequences of the numerous mitochondrial tRNA mutations that result in disease in humans.Human mitochondria are subcellular organelles that produce more than 90% of the energy required by the cell. The mitochondrial genome encodes 13 proteins necessary for energy production, two rRNAs and all of the 22 tRNAs required for the synthesis of these proteins (1, 2). Mammalian mitochondrial tRNAs have several unusual features that distinguish them from canonical tRNAs. In many cases, they lack a number of the conserved or semi-conserved nucleotides that play important roles in creating the L-shaped tertiary structure of prokaryotic and eukaryotic cytoplasmic tRNAs (3). There is little detailed structural information on these tRNAs. No data are currently available that examine the structure of mammalian mitochondrial tRNAs with single nucleotide resolution. However, chemical and enzymatic probing has lead to the idea that these tRNAs have retained the basic cloverleaf structure of canonical tRNAs but that they lack several conserved tertiary interactions leading to a weaker three-dimensional structure (4 -8). In particular, a number of the long range interactions between the Dand T-arms of the tRNAs appear to be missing.All 22 tRNAs that function in mammalian mitochondria are encoded in the mitochondrial DNA. Considerable interest in mitochondrial tRNAs centers on the occurrence of diseases arising from mutations in their genes that lead to maternally inherited genetic diso...

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Mitochondrial tRNA Mutations: Clinical and Functional Perturbations

Abstract: Previously published online as a RNA Biology E-publication:

Cited by 52 publications

References 282 publications

Crystal Structure of Human Mitochondrial PheRS Complexed with tRNAPhe in the Active “Open” State

Crystal Structure of Human Mitochondrial PheRS Complexed with tRNAPhe in the Active “Open” State

Mitochondrial DNA Sequence Variants Associated With Blood Pressure Among 2 Cohorts of Older Adults

A Disease-causing Point Mutation in Human Mitochondrial tRNAMet Results in tRNA Misfolding Leading to Defects in Translational Initiation and Elongation

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