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Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency

Lookup NU author(s): Dr Helen GriffinORCiD, Dr Michele GiuntaORCiD, Benjamin Munro, Dr Wei Wei, Dr Veronika Boczonadi, Dr Angela Pyle, Professor Michael Hanna, Dr Jennifer Duff, Dr Andreas Roos, Professor Hanns Lochmuller, Professor Patrick Chinnery, Professor Rita HorvathORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2020 The Authors Published under the terms of the CC BY 4.0 license. 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.

Publication metadata

Author(s): Hathazi D, Griffin H, Jennings MJ, Giunta M, Powell C, Pearce SF, Munro B, Wei W, Boczonadi V, Poulton J, Pyle A, Calabrese C, Gomez-Duran A, Schara U, Pitceathly RDS, Hanna MG, Joost K, Cotta A, Paim JF, Navarro MM, Duff J, Mattmann A, Chapman K, Servidei S, Della Marina A, Uusimaa J, Roos A, Mootha V, Hirano M, Tulinius M, Giri M, Hoffmann EP, Lochmuller H, DiMauro S, Minczuk M, Chinnery PF, Muller JS, Horvath R

Publication type: Article

Publication status: Published

Journal: EMBO Journal

Year: 2020

Volume: 39

Issue: 23

Print publication date: 01/12/2020

Online publication date: 31/10/2020

Acceptance date: 09/09/2020

Date deposited: 11/11/2020

ISSN (print): 0261-4189

ISSN (electronic): 1460-2075

Publisher: Wiley-VCH Verlag


DOI: 10.15252/embj.2020105364


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