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.

Perli, E., Pisano, A., Pignataro, M.G., Campese, A.F., Pelullo, M., Genovese, I., et al. (2020). Exogenous peptides are able to penetrate human cell and mitochondrial membranes, stabilize mitochondrial tRNA structures, and rescue severe mitochondrial defects. THE FASEB JOURNAL, 34(6), 7675-7686 [10.1096/fj.201903270R].

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

Ghelli, Anna Maria;
2020

Abstract

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.
2020
Perli, E., Pisano, A., Pignataro, M.G., Campese, A.F., Pelullo, M., Genovese, I., et al. (2020). Exogenous peptides are able to penetrate human cell and mitochondrial membranes, stabilize mitochondrial tRNA structures, and rescue severe mitochondrial defects. THE FASEB JOURNAL, 34(6), 7675-7686 [10.1096/fj.201903270R].
Perli, Elena; Pisano, Annalinda; Pignataro, Maria Gemma; Campese, Antonio Francesco; Pelullo, Maria; Genovese, Ilaria; de Turris, Valeria; Ghelli, Ann...espandi
File in questo prodotto:
File Dimensione Formato  
2020 - Perli - Exogenous peptides and tRNA mitochondrial defects - FASEB J.pdf

accesso riservato

Tipo: Versione (PDF) editoriale
Licenza: Licenza per accesso riservato
Dimensione 551.48 kB
Formato Adobe PDF
551.48 kB Adobe PDF   Visualizza/Apri   Contatta l'autore
fsb220504-sup-0006-figs6.tif

accesso riservato

Tipo: Versione (PDF) editoriale
Licenza: Licenza per accesso riservato
Dimensione 123.92 kB
Formato TIFF
123.92 kB TIFF   Visualizza/Apri   Contatta l'autore
fsb220504-sup-0003-figs3.tif

accesso riservato

Tipo: Versione (PDF) editoriale
Licenza: Licenza per accesso riservato
Dimensione 143.04 kB
Formato TIFF
143.04 kB TIFF   Visualizza/Apri   Contatta l'autore
fsb220504-sup-0004-figs4.tif

accesso riservato

Tipo: Versione (PDF) editoriale
Licenza: Licenza per accesso riservato
Dimensione 154.08 kB
Formato TIFF
154.08 kB TIFF   Visualizza/Apri   Contatta l'autore
fsb220504-sup-0005-figs5.tif

accesso riservato

Tipo: Versione (PDF) editoriale
Licenza: Licenza per accesso riservato
Dimensione 129.81 kB
Formato TIFF
129.81 kB TIFF   Visualizza/Apri   Contatta l'autore
fsb220504-sup-0002-figs2.tif

accesso riservato

Tipo: Versione (PDF) editoriale
Licenza: Licenza per accesso riservato
Dimensione 123.64 kB
Formato TIFF
123.64 kB TIFF   Visualizza/Apri   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/764563
Citazioni
  • ???jsp.display-item.citation.pmc??? 5
  • Scopus 6
  • ???jsp.display-item.citation.isi??? 6
social impact