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Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency

Hathazi, D; Griffin, H; Jennings, MJ; Giunta, M; Powell, C; Pearce, SF; Munro, B; ... Horvath, R; + view all (2020) Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency. EMBO Journal , Article e105364. 10.15252/embj.2020105364. Green open access

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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.

Type: Article
Title: Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/embj.2020105364
Publisher version: https://doi.org/10.15252/embj.2020105364
Language: English
Additional information: © 2020 The Authors. Published under the terms of the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).
Keywords: digenic inheritance; homoplasmic tRNA mutation; mitochondrial myopathy; reversible infantile respiratory chain deficiency
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10114358
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