دورية أكاديمية
أعرض في EDS

Pathological mutations promote proteolysis of mitochondrial tRNA-specific 2-thiouridylase 1 (MTU1) via mitochondrial caseinolytic peptidase (CLPP).

التفاصيل البيبلوغرافية
العنوان: Pathological mutations promote proteolysis of mitochondrial tRNA-specific 2-thiouridylase 1 (MTU1) via mitochondrial caseinolytic peptidase (CLPP).
المؤلفون: Ahmad RNR; Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto, 860-8556, Japan.; Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, 980-8575, Japan., Zhang LT; Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, 980-8575, Japan., Morita R; Center for Computational Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan., Tani H; Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, 980-8575, Japan., Wu Y; Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto, 860-8556, Japan., Chujo T; Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto, 860-8556, Japan., Ogawa A; Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, 980-8575, Japan., Harada R; Center for Computational Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan., Shigeta Y; Center for Computational Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan., Tomizawa K; Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto, 860-8556, Japan., Wei FY; Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, 980-8575, Japan.
المصدر: Nucleic acids research [Nucleic Acids Res] 2024 Feb 09; Vol. 52 (3), pp. 1341-1358.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: 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
أسماء مطبوعة: Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.
مواضيع طبية MeSH: Mitochondria*/genetics , Mitochondria*/metabolism , Peptide Hydrolases*/genetics , tRNA Methyltransferases*/genetics , Mitochondrial Proteins*/metabolism, Humans ; Endopeptidase Clp/genetics ; Endopeptidase Clp/metabolism ; Mutation ; Proteolysis ; RNA, Mitochondrial/metabolism ; RNA, Transfer/metabolism
مستخلص: MTU1 controls intramitochondrial protein synthesis by catalyzing the 2-thiouridine modification of mitochondrial transfer RNAs (mt-tRNAs). Missense mutations in the MTU1 gene are associated with life-threatening reversible infantile hepatic failure. However, the molecular pathogenesis is not well understood. Here, we investigated 17 mutations associated with this disease, and our results showed that most disease-related mutations are partial loss-of-function mutations, with three mutations being particularly severe. Mutant MTU1 is rapidly degraded by mitochondrial caseinolytic peptidase (CLPP) through a direct interaction with its chaperone protein CLPX. Notably, knockdown of CLPP significantly increased mutant MTU1 protein expression and mt-tRNA 2-thiolation, suggesting that accelerated proteolysis of mutant MTU1 plays a role in disease pathogenesis. In addition, molecular dynamics simulations demonstrated that disease-associated mutations may lead to abnormal intermolecular interactions, thereby impairing MTU1 enzyme activity. Finally, clinical data analysis underscores a significant correlation between patient prognosis and residual 2-thiolation levels, which is partially consistent with the AlphaMissense predictions. These findings provide a comprehensive understanding of MTU1-related diseases, offering prospects for modification-based diagnostics and novel therapeutic strategies centered on targeting CLPP.
(© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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معلومات مُعتمدة: 18H02599 JSPS; JPMJER2002 ERATO; JPMJFR205Y FOREST; Takeda Science Foundation; Uehara Memorial Foundation; JST
المشرفين على المادة: EC 3.4.21.92 (Endopeptidase Clp)
EC 3.4.- (Peptide Hydrolases)
0 (RNA, Mitochondrial)
9014-25-9 (RNA, Transfer)
EC 2.1.1.61 (TRMU protein, human)
EC 2.1.1.- (tRNA Methyltransferases)
0 (Mitochondrial Proteins)
تواريخ الأحداث: Date Created: 20231219 Date Completed: 20240215 Latest Revision: 20240215
رمز التحديث: 20240215
مُعرف محوري في PubMed: PMC10853782
DOI: 10.1093/nar/gkad1197
PMID: 38113276
قاعدة البيانات: MEDLINE
الوصف
تدمد:1362-4962
DOI:10.1093/nar/gkad1197