المؤلفون: Johanna H.K. Kauppila, Holly L. Baines, Ana Bratic, Marie-Lune Simard, Christoph Freyer, Arnaud Mourier, Craig Stamp, Roberta Filograna, Nils-Göran Larsson, Laura C. Greaves, James B. Stewart

المصدر: Cell Reports, Vol 16, Iss 11, Pp 2980-2990 (2016)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: Mutations of mtDNA are an important cause of human disease, but few animal models exist. Because mammalian mitochondria cannot be transfected, the development of mice with pathogenic mtDNA mutations has been challenging, and the main strategy has therefore been to introduce mutations found in cell lines into mouse embryos. Here, we describe a phenotype-driven strategy that is based on detecting clonal expansion of pathogenic mtDNA mutations in colonic crypts of founder mice derived from heterozygous mtDNA mutator mice. As proof of concept, we report the generation of a mouse line transmitting a heteroplasmic pathogenic mutation in the alanine tRNA gene of mtDNA displaying typical characteristics of classic mitochondrial disease. In summary, we describe a straightforward and technically simple strategy based on mouse breeding and histology to generate animal models of mtDNA-mutation disease, which will be of great importance for studies of disease pathophysiology and preclinical treatment trials.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2211124716311019Test; https://doaj.org/toc/2211-1247Test

الوصول الحر: https://doaj.org/article/c9d60e6d715741ada477ce9887a88f10Test

المؤلفون: Oliver Rackham, Jakob D. Busch, Stanka Matic, Stefan J. Siira, Irina Kuznetsova, Ilian Atanassov, Judith A. Ermer, Anne-Marie J. Shearwood, Tara R. Richman, James B. Stewart, Arnaud Mourier, Dusanka Milenkovic, Nils-Göran Larsson, Aleksandra Filipovska

المصدر: Cell Reports, Vol 16, Iss 7, Pp 1874-1890 (2016)

مصطلحات موضوعية: RNA metabolism, mitochondria, PPR domains, RNA-seq, Biology (General), QH301-705.5

الوصف: The regulation of mitochondrial RNA processing and its importance for ribosome biogenesis and energy metabolism are not clear. We generated conditional knockout mice of the endoribonuclease component of the RNase P complex, MRPP3, and report that it is essential for life and that heart and skeletal-muscle-specific knockout leads to severe cardiomyopathy, indicating that its activity is non-redundant. Transcriptome-wide parallel analyses of RNA ends (PARE) and RNA-seq enabled us to identify that in vivo 5′ tRNA cleavage precedes 3′ tRNA processing, and this is required for the correct biogenesis of the mitochondrial ribosomal subunits. We identify that mitoribosomal biogenesis proceeds co-transcriptionally because large mitoribosomal proteins can form a subcomplex on an unprocessed RNA containing the 16S rRNA. Taken together, our data show that RNA processing links transcription to translation via assembly of the mitoribosome.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2211124716309494Test; https://doaj.org/toc/2211-1247Test

الوصول الحر: https://doaj.org/article/652a730d45964cd69e2050754ec12432Test

المؤلفون: Nils-Göran Larsson, Arnaud Mourier, Christoph Freyer, Ana Bratic, Roberta Filograna, Craig Stamp, Marie-Lune Simard, Johanna H.K. Kauppila, James B. Stewart, Holly L. Baines, Laura C. Greaves

المصدر: Cell Reports
Cell Reports, Vol 16, Iss 11, Pp 2980-2990 (2016)
Cell Rep

مصطلحات موضوعية: 0301 basic medicine, Mitochondrial DNA, Mitochondrial Diseases, Mitochondrial disease, RNA, Transfer, Ala, Disease, Breeding, Mitochondrion, Biology, DNA, Mitochondrial, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Animals, lcsh:QH301-705.5, Gene, Genetics, Transfection, medicine.disease, Phenotype, Heteroplasmy, Clone Cells, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, lcsh:Biology (General), Protein Biosynthesis, Mutation, Female, Cardiomyopathies

الوصف: Summary Mutations of mtDNA are an important cause of human disease, but few animal models exist. Because mammalian mitochondria cannot be transfected, the development of mice with pathogenic mtDNA mutations has been challenging, and the main strategy has therefore been to introduce mutations found in cell lines into mouse embryos. Here, we describe a phenotype-driven strategy that is based on detecting clonal expansion of pathogenic mtDNA mutations in colonic crypts of founder mice derived from heterozygous mtDNA mutator mice. As proof of concept, we report the generation of a mouse line transmitting a heteroplasmic pathogenic mutation in the alanine tRNA gene of mtDNA displaying typical characteristics of classic mitochondrial disease. In summary, we describe a straightforward and technically simple strategy based on mouse breeding and histology to generate animal models of mtDNA-mutation disease, which will be of great importance for studies of disease pathophysiology and preclinical treatment trials.
Graphical Abstract Image 1
Highlights • We present a method to isolate and identify pathogenic mtDNA mutations in mice • We describe a mouse with a pathogenic mutation in the mitochondrial tRNAALA gene • The mice display disrupted mitochondrial translation as a result of the mutation • The mice display molecular and histochemical symptoms of human mitochondrial disease
Kauppila et al. describe a phenotype-based screen in live mice to generate mouse models with pathogenic mtDNA mutations. As proof of concept, they present a mouse with a mutation in the mitochondrial tRNAALA gene that displays molecular and histochemical symptoms of human mitochondrial disease.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8c824f6f9ee2b07b5edd40e78024257aTest
https://doi.org/10.1016/j.celrep.2016.08.037Test

المؤلفون: Tara R. Richman, Stanka Matic, Ilian Atanassov, Dusanka Milenkovic, Judith A. Ermer, Oliver Rackham, Aleksandra Filipovska, James B. Stewart, Jakob D. Busch, Irina M. Kuznetsova, Anne-Marie J. Shearwood, Nils-Göran Larsson, Arnaud Mourier, Stefan J. Siira

المصدر: Cell Reports
Cell Rep
Cell Reports, Vol 16, Iss 7, Pp 1874-1890 (2016)

مصطلحات موضوعية: 0301 basic medicine, Ribosomal Proteins, PPR domains, Mitochondrial RNA processing, Transcription, Genetic, TRNA processing, Ribosome biogenesis, Biology, Cell Fractionation, General Biochemistry, Genetics and Molecular Biology, Mitochondria, Heart, Ribonuclease P, Mitochondrial Proteins, Mitochondrial Ribosomes, 03 medical and health sciences, Mice, 0302 clinical medicine, RNA, Transfer, RNA, Ribosomal, 16S, Animals, RNA Processing, Post-Transcriptional, Muscle, Skeletal, lcsh:QH301-705.5, RNA metabolism, Genetics, Mitochondrial ribosome assembly, Mice, Knockout, Organelle Biogenesis, Myocardium, RNA, Non-coding RNA, Cell biology, mitochondria, Mice, Inbred C57BL, 030104 developmental biology, lcsh:Biology (General), RNA editing, Protein Biosynthesis, Transfer RNA, RNA-seq, Cardiomyopathies, Transcriptome, 030217 neurology & neurosurgery

الوصف: Summary The regulation of mitochondrial RNA processing and its importance for ribosome biogenesis and energy metabolism are not clear. We generated conditional knockout mice of the endoribonuclease component of the RNase P complex, MRPP3, and report that it is essential for life and that heart and skeletal-muscle-specific knockout leads to severe cardiomyopathy, indicating that its activity is non-redundant. Transcriptome-wide parallel analyses of RNA ends (PARE) and RNA-seq enabled us to identify that in vivo 5′ tRNA cleavage precedes 3′ tRNA processing, and this is required for the correct biogenesis of the mitochondrial ribosomal subunits. We identify that mitoribosomal biogenesis proceeds co-transcriptionally because large mitoribosomal proteins can form a subcomplex on an unprocessed RNA containing the 16S rRNA. Taken together, our data show that RNA processing links transcription to translation via assembly of the mitoribosome.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8c1914052604de7b1cbe554b15867e94Test
https://pubmed.ncbi.nlm.nih.gov/27498866Test