title: Short peptides from leucyl-tRNA synthetase rescue disease-causing mitochondrial tRNA point mutations.
abstract: 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-tRNA(Leu(UUR)) or with mutations in the mt-tRNA(Ile), 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-tRNA(Lys), 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-tRNA(Leu(UUR)) and mt-tRNA(Lys), and stabilize mutant mt-tRNA(Leu(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.
authors.affiliation: Department of Radiology, Oncology and Pathology.
authors.forename: Elena
authors.initials: E
authors.lastname: Perli
authors.affiliation: Department of Biochemical Sciences "A. Rossi Fanelli".
authors.forename: Annarita
authors.initials: A
authors.lastname: Fiorillo
authors.affiliation: Department of Radiology, Oncology and Pathology.
authors.forename: Carla
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Department of Radiology, Oncology and Pathology.
authors.forename: Annalinda
authors.initials: A
authors.lastname: Pisano
authors.affiliation: Department of Biology and Biotechnologies 'Charles Darwin' and Pasteur Institute-Cenci Bolognetti Foundation, Rome 00161, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Montanari
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Grazioli
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Antonio F
authors.initials: AF
authors.lastname: Campese
authors.affiliation: Department of Biochemical Sciences "A. Rossi Fanelli".
authors.forename: Patrizio
authors.initials: P
authors.lastname: Di Micco
authors.affiliation: Wellcome Trust Center for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE1 7RU, UK and.
authors.forename: Helen A
authors.initials: HA
authors.lastname: Tuppen
authors.affiliation: Department of Biochemical Sciences "A. Rossi Fanelli".
authors.forename: Ilaria
authors.initials: I
authors.lastname: Genovese
authors.affiliation: Department of Biochemical Sciences "A. Rossi Fanelli".
authors.forename: Elena
authors.initials: E
authors.lastname: Poser
authors.affiliation: Department of Radiology, Oncology and Pathology.
authors.forename: Carmela
authors.initials: C
authors.lastname: Preziuso
authors.affiliation: Wellcome Trust Center for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE1 7RU, UK and.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: National Research Council of Italy, Institute of Molecular Biology and Pathology, Rome 00185, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Morea
authors.affiliation: National Research Council of Italy, Institute of Molecular Biology and Pathology, Rome 00185, Italy giulia.damati@uniroma1.it gianni.colotti@uniroma1.it.
authors.forename: Gianni
authors.initials: G
authors.lastname: Colotti
authors.affiliation: Department of Radiology, Oncology and Pathology, Pasteur Institute-Cenci Bolognetti Foundation, Rome 00161, Italy, giulia.damati@uniroma1.it gianni.colotti@uniroma1.it.
authors.forename: Giulia
authors.initials: G
authors.lastname: d'Amati
mesh_terms: D000595:Amino Acid Sequence; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D017241:MELAS Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017243:MERRF Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010641:Phenotype; D017354:Point Mutation; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D012356:RNA, Transfer, Leu / Q000378:metabolism; D012357:RNA, Transfer, Lys / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D010455:Peptides; D012356:RNA, Transfer, Leu; D012357:RNA, Transfer, Lys; D000604:Amino Acyl-tRNA Synthetases; C549096:LARS2 protein, human