Human mitochondrial tRNAs in health and disease

Florentz, Catherine; Sohm, Bénédicte; Tryoen-Tóth, Petra; Pütz, Joern; Sissler, Marie

doi:10.1007/s00018-003-2343-1

Cited by 235 publications

(220 citation statements)

References 136 publications

(128 reference statements)

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“…A number of mutations in the mitochondrial tRNA genes of humans are associated with myoclonic epilepsy with ragged red fibers (MERRF) (30). Generally, these mutations lead to a drastic reduction in the synthesis of mitochondrial proteins with concomitant reduction in mitochondrial respiration and thus reduced ability to efficiently generate ATP.…”

Section: Rescue Of Trna Import Into Merrf Mitochondria By Addition Ofmentioning

confidence: 99%

Mammalian mitochondria have the innate ability to import tRNAs by a mechanism distinct from protein import

Rubio

Rinehart

Krett

et al. 2008

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

139

114

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Mitochondrial genomes generally encode a minimal set of tRNAs necessary for protein synthesis. However, a number of eukaryotes import tRNAs from the cytoplasm into their mitochondria. For instance, Saccharomyces cerevisiae imports cytoplasmic tRNA Gln into the mitochondrion without any added protein factors. Here, we examine the existence of a similar active tRNA import system in mammalian mitochondria. We have used subcellular RNA fractions from rat liver and human cells to perform RT-PCR with oligonucleotide primers specific for nucleus-encoded tRNA CUG Gln and tRNA UUG Gln species, and we show that these tRNAs are present in rat and human mitochondria in vivo. Import of in vitro transcribed tRNAs, but not of heterologous RNAs, into isolated mitochondria also demonstrates that this process is tRNA-specific and does not require the addition of cytosolic factors. Although this in vitro system requires ATP, it is resistant to inhibitors of the mitochondrial electrochemical gradient, a key component of protein import. tRNA Gln import into mammalian mitochondria proceeds by a mechanism distinct from protein import. We also show that both tRNA Gln species and a bacterial pre-tRNA Asp can be imported in vitro into mitochondria isolated from myoclonic epilepsy with ragged-red fiber cells if provided with sufficient ATP (2 mM). This work suggests that tRNA import is more widespread than previously thought and may be a universal trait of mitochondria. Mutations in mitochondrial tRNA genes have been associated with human disease; the tRNA import system described here could possibly be exploited for the manipulation of defective mitochondria.human ͉ MERFF D ifferent protein-synthesizing systems exist in the cytoplasm and organelles (mitochondria and chloroplasts) of eukaryotic cells. Reflecting the evolutionary origin of the organelle, the mitochondrial system is bacteria-like (1, 2). For instance, the tRNAs and aminoacyl-tRNA synthetases present in the mitochondria are closely related to their bacterial counterparts. The mitochondrial genome of higher eukaryotes encodes all of the tRNA species necessary for protein synthesis (3), whereas the aminoacyl-tRNA synthetases are nucleus-encoded and imported into the organelle. The mitochondrial protein-synthesizing system is important for the synthesis of a number of proteins for multienzyme complexes involved in oxidative phosphorylation (1). Since the original suggestion 40 years ago (4), tRNA import into mitochondria has been demonstrated in Tetrahymena, trypanosomatids, yeast, plants, and marsupials (reviewed in refs. 5 and 6). The detailed nature of the different tRNA import mechanisms is not yet known; however, ATP hydrolysis is always required. In the yeast system, the importance of some mitochondrial membrane proteins as well as of specific cytosolic proteins (enolase and lysyl-tRNA synthetase) has been established (reviewed in refs. 5 and 6). After the early observation of the presence of a cytoplasmic tRNA CUU Lys in Saccharomyces cerevisiae mitochondria (7), import o...

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Section: Rescue Of Trna Import Into Merrf Mitochondria By Addition Ofmentioning

confidence: 99%

Mammalian mitochondria have the innate ability to import tRNAs by a mechanism distinct from protein import

Rubio

Rinehart

Krett

et al. 2008

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

139

114

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“…21,22) The 5' end of the flanking sequence is 4401A/AG-TAAG in the tRNA Met gene, whereas the 5'end of the flanking sequence is 4401T/TGAGAT in the tRNA Gln gene. 23) In fact, the processing of mt-tRNAs requires the precise endonucleolytic cleavage at both the 3' and 5' ends catalyzed by RNase P and 3' endonuclease. 24,25) Thus, the A4401G mutation may affect the reaction efficiency of the RNase P involved in tRNA Met and tRNA Gln 5' end metabolism.…”

Section: Discussionmentioning

confidence: 99%

The Mitochondrial tRNAAla T5655C Mutation May Modulate the Phenotypic Expression of tRNAMet and tRNAGln A4401G Mutation in a Han Chinese Family With Essential Hypertension

Chen

Huang

et al. 2017

Int. Heart J.

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SummaryMutations in mitochondrial DNA are associated with the pathogenesis of essential hypertension. We report here the clinical, genetic, and molecular characterization of a three-generation Han Chinese family with essential hypertension. Most strikingly, this family exhibited a high penetrance of essential hypertension. Sequence analysis of the mitochondrial genome showed the presence of a homoplasmic T5655C mutation in tRNA Ala , together with the A4401G mutation in the adjacent region between tRNA Met and tRNA Gln. Notably, the T5655C mutation was localized at the acceptor arm of tRNA Ala , disrupted the high conserved base-pairing (1A-72T), and may impair the tRNA function. Moreover, the A4401G mutation was reported to decrease the steady-state level of tRNA Met and tRNA Gln, and consequently caused the mitochondrial dysfunction responsible for hypertension. Taken together, the combination of T5655C and A4401G mutations in mitochondrial tRNA genes may account for the high penetrance and expressivity of hypertension in this Chinese family. Thus, our findings may provide new insight into the pathogenesis of this disorder. (Int Heart J 2017; 58: 95-99)

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“…mt-tRNA point mutations have been associated with a diverse range of clinical phenotypes, including epilepsy, deafness, diabetes, cardiomyopathy, and encephalopathy (Florentz et al, 2003;Yarham et al, 2010). To date, over 200 mt-tRNA mutations have been linked to mitochondrial disease, but sufficient evidence to justify a classification of "definitely pathogenic" exists for less than half of these (Yarham et al, 2011), demonstrating the difficulties faced when characterizing potentially pathogenic variants.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial tRNALeu(CUN) A12307G variant may not be associated pancreatic cancer

Huang

Chen

et al. 2016

Genet. Mol. Res.

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Human mitochondrial tRNAs in health and disease

Cited by 235 publications

References 136 publications

Mammalian mitochondria have the innate ability to import tRNAs by a mechanism distinct from protein import

Mammalian mitochondria have the innate ability to import tRNAs by a mechanism distinct from protein import

The Mitochondrial tRNA<sup>Ala</sup> T5655C Mutation May Modulate the Phenotypic Expression of tRNA<sup>Met</sup> and tRNA<sup>Gln</sup> A4401G Mutation in a Han Chinese Family With Essential Hypertension

Mitochondrial tRNALeu(CUN) A12307G variant may not be associated pancreatic cancer

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