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Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency

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dc.contributor.author Hathazi, Denisa
dc.contributor.author Lochmüller, Hanns
dc.contributor.author Horvath, Rita
dc.date.accessioned 2020-11-13T07:31:02Z
dc.date.available 2020-11-13T07:31:02Z
dc.date.issued 2020
dc.identifier.citation Hathazi D, Griffin H, Jennings MJ, Giunta M, Powell C, Pearce SF et al. Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency. EMBO J. 2020 Dec 1;39(23):e105364. DOI: 10.15252/embj.2020105364
dc.identifier.issn 0261-4189
dc.identifier.uri http://hdl.handle.net/10230/45751
dc.description.abstract Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6-months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt-tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease.
dc.description.sponsorship RH was supported by the European Research Council [309548], the Wellcome Investigator Award [109915/Z/15/Z]. the Medical Research Council (UK) [MR/N025431/1]; the Wellcome Trust Pathfinder Scheme [201064/Z/16/Z], the Newton Fund [UK/Turkey, MR/N027302/1], the Lily Foundation and the Evelyn Trust.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher EMBO Press
dc.relation.ispartof EMBO J. 2020 Dec 1;39(23):e105364
dc.rights © 2020 The Authors Published under the terms of the CC BY 4.0 license (http://creativecommons.org/licenses/by/4.0/). This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.15252/embj.2020105364
dc.subject.keyword Digenic inheritance
dc.subject.keyword Homoplasmic tRNA mutation
dc.subject.keyword Mitochondrial myopathy
dc.subject.keyword Reversible infantile respiratory chain deficiency
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309548
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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