The yeast model suggests the use of short peptides derived from mt LeuRS for the therapy of diseases due to mutations in several mt tRNAs

Micco, Patrizio Di; D'Orsi, Mario Fazzi; Morea, Veronica; Frontali, Laura; Francisci, Silvia; Montanari, Arianna

doi:10.1016/j.bbamcr.2014.09.011

Cited by 5 publications

(13 citation statements)

References 43 publications

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“…Importantly, the observation that the rescuing effect of the mt‐LeuRS‐derived sequences is exerted not only on the cognate mt‐tRNA Leu(UUR) but also on the non‐cognate mt‐tRNA Lys , led us to propose that these sequences may be active on a large spectrum of human mt‐tRNA mutants. Indeed, transfection of nucleotide sequences encoding for both β32_33 and β30_31 peptides has been demonstrated to be able to rescue the phenotype of a large panel of mt‐tRNA mutants in the yeast model 9 …”

Section: Introductionmentioning

confidence: 99%

Exogenous peptides are able to penetrate human cell and mitochondrial membranes, stabilize mitochondrial tRNA structures, and rescue severe mitochondrial defects

et al. 2020

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Mutations in mitochondrial transfer RNA (mt‐tRNA) genes are responsible for a wide range of syndromes, for which no effective treatment is available. We previously reported that transfection of the nucleotide sequence encoding for the 16‐residue β32_33 peptide from mitochondrial leucyl‐tRNA synthetase ameliorates the cell phenotype caused by the mitochondrial tRNA mutations. In this work, we demonstrated that both the β32_33 peptide linked with the known (L)‐Phe‐(D)‐Arg‐(L)‐Phe‐(L)‐Lys (FrFK) mitochondrial penetrating sequence and, strikingly, the β32_33 peptide per se, are able to penetrate both the plasma and mitochondrial membranes and exert the rescuing activity when exogenously administered to cells bearing the mutations m.3243A > G and m.8344A > G. These mutations are responsible for the most common and severe mt‐tRNA‐related diseases. In addition, we dissected the molecular determinants of constructs activity by showing that both the order of amino acids along the sequence and presence of positive charges are essential determinants of the peptide activity in cells and mt‐tRNA structures stabilization in vitro. In view of future in vivo studies, this information may be required to design of β32_33 peptide‐mimetic derivatives. The β32_33 and FrFK‐β32_33 peptides are, therefore, promising molecules for the development of therapeutic agents against diseases caused by the mt‐tRNA point mutations.

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Section: Introductionmentioning

confidence: 99%

Exogenous peptides are able to penetrate human cell and mitochondrial membranes, stabilize mitochondrial tRNA structures, and rescue severe mitochondrial defects

et al. 2020

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“…The aim of the present study is to evaluate the cellular internalization of multi-walled carbon nanotubes (MWCNTs) chemically conjugated or not with the peptide sequence previously demonstrated to suppress the defective growth phenotype due to mt tRNA mutations. Indeed studies on the yeast model have recently shown that overexpressed mt LeuRS-Cterm, β30_31 and β32_33 peptides (15 and 16 amino acids long, respectively) suppressed the respiratory defects due to mutations in mt tRNAs aminoacylated by class II, as well as class I mt aaRS 5,12 . The suppression capability of these plasmid constructs was also confirmed in human cells 10,11,13 .…”

Section: Resultsmentioning

confidence: 99%

“…Overexpression of the oligonucleotide sequences coding for the peptides β30_31 (MAVLINNKACGKIPV) or β32_33 (KKSFLSPRTALINFLV), comprised within the orthologous carboxy-terminal domain of human LeuRS, corrected the defects associated with several point mutations in yeast mt tRNA 5,12 . This activity has been obtained also in transfected cybrid lines bearing substitution in tRNA Leu(UUR) and tRNA Lys 13 .…”

Section: Discussionmentioning

confidence: 99%

“…In vitro experiments demonstrated that mt LeuRS-Cterm peptide was able to directly and specifically interact either with human cognate mt tRNA Leu(UUR) either with non-cognate mt tRNA Ile even if with 4-fold lower affinity 11 . Moreover we have shown that the β30_31 peptide specifically interacts with cognate and non-cognate mt tRNAs 5,13 . The demonstration that the catalytic function of mt LeuRS is not required for rescuing activity and that the interaction occurring between the mt LeuRS-Cterm domain and the cognate or non-cognate tRNA in in vitro shift binding experiment 5 strongly point to a 'chaperone-like' molecular effect.…”

Section: Introductionmentioning

confidence: 86%

“…We have also identified the minimal sequences of the mt LeuRS-Cterm responsible for suppression. The short isolated peptides of 15 and 16 amino acids (named β30_31 and β32_33) were endowed with the same suppressing activity of the full Cterm when overexpressed in a broad range of different yeast mt tRNA mutants 5,12 . In vitro experiments demonstrated that mt LeuRS-Cterm peptide was able to directly and specifically interact either with human cognate mt tRNA Leu(UUR) either with non-cognate mt tRNA Ile even if with 4-fold lower affinity 11 .…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the efficacy of carbon nanotubes for delivering peptides into mitochondria

et al. 2016

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Mitochondrial (mt) diseases are devastating neurodegenerative pathologies due tomutations in nuclear or mt genes. Among mtDNA pathogenic mutations, more than one half have been identified in transfer RNA (tRNA) genes. These are responsible for a wide range of pathologies including myopathies, encephalopathies, cardiomyopathies and deafness for which no effective treatment is available at present. Therefore, new strategies to suppress their damaging effects are required to envisage therapeutic approaches for these diseases. Here we report data for carbon nanotube (CNT) derivatives showing that the conjugates bearing a specific peptide sequence are able to target the mitochondria in yeast and human monocyte cells while the control derivative without the peptide diffuses into the cytoplasm. Moreover the compounds do not affect cellular viability and cytotoxicity both in vitro and in vivo. Toxicity of the constructs is also assessed on the simple pluricellular model Caenorhabditis elegans

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Short peptides from leucyl-tRNA synthetase rescue disease-causing mitochondrial tRNA point mutations

Perli¹,

Fiorillo²,

Giordano³

et al. 2015

Hum. Mol. Genet.

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Mutations in mitochondrial (mt) genes coding for mt-tRNAs are responsible for a range of syndromes, for which no effective treatment is available. We recently showed that the carboxy-terminal domain (Cterm) of human mt-leucyl tRNA synthetase rescues the pathologic phenotype associated either with the m.3243A>G mutation in mt-tRNALeu(UUR) or with mutations in the mt-tRNAIle, both of which are aminoacylated by Class I mt-aminoacyl-tRNA synthetases (mt-aaRSs). Here we show, by using the human transmitochondrial cybrid model, that the Cterm is also able to improve the phenotype caused by the m.8344A>G mutation in mt-tRNALys, aminoacylated by a Class II aaRS. Importantly, we demonstrate that the same rescuing ability is retained by two Cterm-derived short peptides, β30_31 and β32_33, which are effective towards both the m.8344A>G and the m.3243A>G mutations. Furthermore, we provide in vitro evidence that these peptides bind with high affinity wild-type and mutant human mt-tRNALeu(UUR) and mt-tRNALys, and stabilize mutant mt-tRNALeu(UUR). In conclusion, we demonstrate that small Cterm-derived peptides can be effective tools to rescue cellular defects caused by mutations in a wide range of mt-tRNAs.

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The yeast model suggests the use of short peptides derived from mt LeuRS for the therapy of diseases due to mutations in several mt tRNAs

Cited by 5 publications

References 43 publications

Exogenous peptides are able to penetrate human cell and mitochondrial membranes, stabilize mitochondrial tRNA structures, and rescue severe mitochondrial defects

Exogenous peptides are able to penetrate human cell and mitochondrial membranes, stabilize mitochondrial tRNA structures, and rescue severe mitochondrial defects

Evaluation of the efficacy of carbon nanotubes for delivering peptides into mitochondria

Short peptides from leucyl-tRNA synthetase rescue disease-causing mitochondrial tRNA point mutations

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