학술논문
Aberrant RNA processing contributes to the pathogenesis of mitochondrial diseases in trans-mitochondrial mouse model carrying mitochondrial tRNALeu(UUR) with a pathogenic A2748G mutation.
Document Type
Academic Journal
Author
Tani H; Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.; Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Aoba-ku, Sendai, Miyagi 980-8575, Japan.; Ishikawa K; Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.; Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.; Tamashiro H; Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.; Ogasawara E; Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan.; Yasukawa T; Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.; Department of Pathology and Oncology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.; Matsuda S; Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Aoba-ku, Sendai, Miyagi 980-8575, Japan.; Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.; Shimizu A; Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University, Jonan-ku, Fukuoka, Fukuoka 814-0180, Japan.; Kang D; Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.; Kashiigaoka Rehabilitation Hospital, Higashi-ku, Fukuoka, Fukuoka 813-0002, Japan.; Hayashi JI; Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.; Wei FY; Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Aoba-ku, Sendai, Miyagi 980-8575, Japan.; Nakada K; Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.; Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.
Source
Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
Subject
Language
English
Abstract
Mitochondrial tRNAs are indispensable for the intra-mitochondrial translation of genes related to respiratory subunits, and mutations in mitochondrial tRNA genes have been identified in various disease patients. However, the molecular mechanism underlying pathogenesis remains unclear due to the lack of animal models. Here, we established a mouse model, designated 'mito-mice tRNALeu(UUR)2748', that carries a pathogenic A2748G mutation in the tRNALeu(UUR) gene of mitochondrial DNA (mtDNA). The A2748G mutation is orthologous to the human A3302G mutation found in patients with mitochondrial diseases and diabetes. A2748G mtDNA was maternally inherited, equally distributed among tissues in individual mice, and its abundance did not change with age. At the molecular level, A2748G mutation is associated with aberrant processing of precursor mRNA containing tRNALeu(UUR) and mt-ND1, leading to a marked decrease in the steady-levels of ND1 protein and Complex I activity in tissues. Mito-mice tRNALeu(UUR)2748 with ≥50% A2748G mtDNA exhibited age-dependent metabolic defects including hyperglycemia, insulin insensitivity, and hepatic steatosis, resembling symptoms of patients carrying the A3302G mutation. This work demonstrates a valuable mouse model with an inheritable pathological A2748G mutation in mt-tRNALeu(UUR) that shows metabolic syndrome-like phenotypes at high heteroplasmy level. Furthermore, our findings provide molecular basis for understanding A3302G mutation-mediated mitochondrial disorders.
(© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
(© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)