Exogenous peptides are able to penetrate human cell and mitochondrial membranes, stabilize mitochondrial tRNA structures, and rescue severe mitochondrial defects.
mitochondrial (mt) diseases
mitochondrial targeting
rescuing peptides
transfer RNA (tRNA) point mutations
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
27
12
2019
revised:
04
03
2020
accepted:
24
03
2020
pubmed:
19
4
2020
medline:
20
1
2021
entrez:
19
4
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32304340
doi: 10.1096/fj.201903270R
doi:
Substances chimiques
Amino Acids
0
Peptides
0
RNA, Transfer
9014-25-9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7675-7686Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
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