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Human mitochondrial diseases caused by lack of taurine modification in mitochondrial tRNAs

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Abstract Mitochondrial DNA mutations that cause mitochondrial dysfunction are responsible for a wide spectrum of human diseases, referred to as mitochondrial diseases. Pathogenic point mutations are found frequently in genes encoding mitochondrial (mt) tRNAs, indicating that impaired functioning of mutant mt tRNAs is the primary cause of mitochondrial dysfunction. Our previous studies revealed the absence of posttranscriptional taurine modification at the anticodon wobble uridine in mutant mt tRNAs isolated from cells derived from patients with two major classes of mitochondrial diseases, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes) and MERRF (myoclonus epilepsy associated with ragged red fibers). Defective taurine modification of the mutant mt tRNAs results in a deficiency in protein synthesis as the cognate codons of the mutant mt tRNA cannot be decoded. These findings represent the first evidence of a molecular pathogenesis caused by an RNA modification disorder. WIREs RNA 2011 2 376–386 DOI: 10.1002/wrna.65 This article is categorized under: RNA-Based Catalysis > Miscellaneous RNA-Catalyzed Reactions RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Processing > tRNA Processing

Chemical structures of two taurine‐containing uridines.

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Schematic depiction of the MELAS decoding disorder and rescue by a G12300A suppressor tRNA. In normal cells, mt tRNALeu(UUR) and tRNALeu(CUN) decode UUR and CUN codons, respectively (left). In pathogenic cells with the MELAS A3243G mutation, the severe reduction in decoding activity of the UUG codon is caused by the absence of τm5U modification in mt tRNALeu(UUR). Revertant cells contain a suppressor mt tRNALeu(CUN) with a G12300A mutation. The suppressor tRNA with an unmodified wobble uridine translates only the UUA codon, whereas the modified version is the only species capable of decoding the UUG codon because of the stabilization of the U:G wobble basepair. The remaining wild‐type mt tRNALeu(CUN) is still responsible for decoding CUN codons (right).

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Crystal structures of an anticodon stem–loop (ASL) with τm5U interacting with either UUA or UUG in the ribosomal A‐site. (a) Unbiased difference Fourier electron density maps for the ASL with τm5UAA anticodon and mRNA with UUG codon (green mesh). The 5′ part of the ASL is not visible. (b) The τm5U‐A basepair along with unbiased difference Fourier electron density maps (green mesh). The basepair refined into a position with a slightly distorted Watson–Click geometry. A weak electron density for the sulfonic acid group was visible at this contour level. (c) The τm5U:G basepair with unbiased difference Fourier electron density maps (green mesh). Although the electron density is not very strong, it does exclude the possibility that the basepair adopts G:U wobble geometry (compare the modeled G:U basepair in transparent gray). (d) Comparison of the stacking interaction between a modeled G:U wobble basepair and the τm5U:G basepair. τm5U has a more favorable stacking interaction with A35 than an unmodified base would have.

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Pathogenic point mutations in human mt tRNAsLeu(UUR) that result in deficient wobble taurine modification or have no effect. (a) MELAS mutations that cause the wobble modification deficiency. (b) Mutations not causing the wobble modification deficiency. The nucleotide modifications are: m1A, 1‐methyladenosine; t6A, N6‐threoninocarbonyladenosine; m1G, 1‐methylguanosine; m2G, 2‐methylguanosine; Ψ, pseudouridine; T, ribothymidine; D, dihydrouridine; m5C, 5‐methylcytidine.47 Mitochondrial myopathy (MM), chronic progressive external ophthalmoplegia (CPEO), and maternally inherited mitochondrial myopathy and cardiomyopathy (MMC).

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Distinct patterns of codon recognition found in mutant tRNAs with no wobble modification. (a) Pathogenic point mutations (A3243G, G3244A, T3258C, T3271C, and T3291C) in mutant tRNALeu(UUR) from MELAS patients causes a τm5U‐modification deficiency that results in a UUG codon‐specific translational defect. (b) The MERRF A8344G mutation also causes a τm5s2U‐modification deficiency that results in a translational defect for both cognate codons (AAA and AAG).

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Mitochondrial tRNA mutations and disease

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RNA Processing > tRNA Processing
RNA-Based Catalysis > Miscellaneous RNA-Catalyzed Reactions
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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