TRMT5 Mutations Cause a Defect in Post-transcriptional Modification of Mitochondrial tRNA Associated with Multiple Respiratory-Chain Deficiencies

Powell, Christopher A.; Kopajtich, Robert; D’Souza, Aaron R.; Rorbach, Joanna; Kremer, Laura S.; Husain, Ralf A.; Dallabona, Cristina; Donnini, Claudia; Alston, Charlotte L.; Griffin, Helen; Pyle, Angela; Chinnery, Patrick F.; Strom, Tim M.; Meitinger, Thomas; Rodenburg, Richard J.; Schottmann, Gudrun; Schuelke, Markus; Romain, Nadine; Haller, Ronald G.; Ferrero, Ileana; Haack, Tobias B.; Taylor, Robert W.; Prokisch, Holger; Minczuk, Michal

doi:10.1016/j.ajhg.2015.06.011

Cited by 88 publications

(92 citation statements)

References 46 publications

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“…Reverse transcription primer extension was performed as described previously (38). Briefly, DNA oligonucleotides were 5′-radiolabeled using [γ- 32 P]ATP and T4 polynucleotide kinase; annealed to 1 μg of CMC/HO − -modified RNA in a 10-μl reaction containing 10 m m Tris-HCl, pH 8.0, and 1 m m EDTA at 80 °C for 2 min; and cooled slowly in a PCR block.…”

Section: Methodsmentioning

confidence: 99%

The Pseudouridine Synthase RPUSD4 Is an Essential Component of Mitochondrial RNA Granules

Zaganelli

Rebelo-Guiomar

Maundrell

et al. 2017

Journal of Biological Chemistry

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Mitochondrial gene expression is a fundamental process that is largely dependent on nuclear-encoded proteins. Several steps of mitochondrial RNA processing and maturation, including RNA post-transcriptional modification, appear to be spatially organized into distinct foci, which we have previously termed mitochondrial RNA granules (MRGs). Although an increasing number of proteins have been localized to MRGs, a comprehensive analysis of the proteome of these structures is still lacking. Here, we have applied a microscopy-based approach that has allowed us to identify novel components of the MRG proteome. Among these, we have focused our attention on RPUSD4, an uncharacterized mitochondrial putative pseudouridine synthase. We show that RPUSD4 depletion leads to a severe reduction of the steady-state level of the 16S mitochondrial (mt) rRNA with defects in the biogenesis of the mitoribosome large subunit and consequently in mitochondrial translation. We report that RPUSD4 binds 16S mt-rRNA, mt-tRNAMet, and mt-tRNAPhe, and we demonstrate that it is responsible for pseudouridylation of the latter. These data provide new insights into the relevance of RNA pseudouridylation in mitochondrial gene expression.

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Section: Methodsmentioning

confidence: 99%

The Pseudouridine Synthase RPUSD4 Is an Essential Component of Mitochondrial RNA Granules

Zaganelli

Rebelo-Guiomar

Maundrell

et al. 2017

Journal of Biological Chemistry

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“…TRMT5 is known to be localized in the mitochondria (although not annotated in MitoCarta 2.0). Mutations in this gene causes defects in the post‐translational modification of mitochondrial tRNAs, leading to a combined OXPHOS deficiency (MIM #616539) …”

Section: Alternative Approaches To Identify Novel Mitochondrial Genesmentioning

confidence: 99%

Mining for mitochondrial mechanisms: Linking known syndromes to mitochondrial function

Panneman¹,

Smeitink²,

Rodenburg³

2017

Clinical Genetics

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Mitochondrial disorders (MDs) are caused by defects in 1 or multiple complexes of the oxidative phosphorylation (OXPHOS) machinery. MDs are associated with a broad range of clinical signs and symptoms, and have considerable clinical overlap with other neuromuscular syndromes. This overlap might be due to involvement of mitochondrial pathways in some of these non-mitochondrial syndromes. Here, we give an overview of around 25 non-mitochondrial syndromes, diagnosed in patients who were initially suspected to have a MD on the basis of clinical and biochemical parameters. In addition, we highlight the mitochondrial connections of 6 of these non-mitochondrial syndromes (eg, Rett syndrome and Dravet syndrome) diagnosed in multiple patients. Further research to unravel the interplay between these genes and mitochondria may help to increase knowledge on these syndromes. Additionally, it may open new avenues for research on pathways interacting with mitochondrial function in order to find new targets for therapeutics to treat MDs. The data presented in this review underline the importance of careful assessment of clinical, genetic, and biochemical data in all patients suspected of a neuromuscular syndrome, and highlights the importance of the role of clinical geneticists, physicians, and clinical biochemists in recognizing the possible mitochondrial connection of non-mitochondrial syndromes.

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“…The reverse transcription primer extension (RT-PEx) was as in ref. 20, the specific 5′ 32 P-labeled primer (0.1 pmol) was incubated with 0.5-1 μg of the RNA isolated from sucrose gradient fractions and subjected to reverse transcription reactions, as described by ref. 21.…”

Section: Methodsmentioning

confidence: 99%

Human mitochondrial ribosomes can switch their structural RNA composition

Rorbach

Gao

Powell

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The recent developments in cryo-EM have revolutionized our access to previously refractory structures. In particular, such studies of mammalian mitoribosomes have confirmed the absence of any 5S rRNA species and revealed the unexpected presence of a mitochondrially encoded tRNA (mt-tRNA) that usurps this position. Although the cryo-EM structures resolved the conundrum of whether mammalian mitoribosomes contain a 5S rRNA, they introduced a new dilemma: Why do human and porcine mitoribosomes integrate contrasting mt-tRNAs? Human mitoribosomes have been shown to integrate mt-tRNAVal compared with the porcine use of mt-tRNA Phe . We have explored this observation further. Our studies examine whether a range of mt-tRNAs are used by different mammals, or whether the mt-tRNA selection is strictly limited to only these two species of the 22 tRNAs encoded by the mitochondrial genome (mtDNA); whether there is tissue-specific variation within a single organism; and what happens to the human mitoribosome when levels of the mt- Mammalian mitoribosomes differ considerably from other ribosomes, primarily because of a reversed protein:RNA mass ratio, such that proteins predominate. Of the 80 known mitoribosomal proteins, 36 are mitospecific and lack bacterial orthologs, and those with orthologs often carry mitospecific extensions (1). Further idiosyncrasies have been revealed by recent subnanometer-resolution cryo-EM structures, which simultaneously resolved a long-debated question concerning mitoribosomal rRNA content (1, 2). Until recently, mammalian mitoribosomes were considered divergent by containing only one rRNA species per subunit, although the potential presence of the 5S species in the mitochondrial large subunit (mt-LSU) remained a contentious issue (3). Recent data have shown that there is indeed a third RNA moiety present in mammalian mitoribosomes.

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TRMT5 Mutations Cause a Defect in Post-transcriptional Modification of Mitochondrial tRNA Associated with Multiple Respiratory-Chain Deficiencies

Cited by 88 publications

References 46 publications

The Pseudouridine Synthase RPUSD4 Is an Essential Component of Mitochondrial RNA Granules

The Pseudouridine Synthase RPUSD4 Is an Essential Component of Mitochondrial RNA Granules

Mining for mitochondrial mechanisms: Linking known syndromes to mitochondrial function

Human mitochondrial ribosomes can switch their structural RNA composition

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