Dataset Information

Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency

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. The spontaneous recovery in infants with digenic mutations is modulated by changes in amino acid availability in a multi-step process. First, the integrated stress-response associated with increased FGF21 and GDF15 expression enhances catabolism via β-oxidation and the TCA cycle increasing the availability of amino acids. In the second phase mitochondrial biogenesis increases via mTOR activation, leading to improved mitochondrial translation and recovery. 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skeletal Muscle

DISEASE(S): Cytochrome-c Oxidase Deficiency Disease

SUBMITTER: Denisa Hathazi

LAB HEAD: Rita Horvath

PROVIDER: PXD020181 | Pride | 2020-10-13

REPOSITORIES: Pride

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Publications

Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency.

Hathazi Denisa D Griffin Helen H Jennings Matthew J MJ Giunta Michele M Powell Christopher C Pearce Sarah F SF Munro Benjamin B Wei Wei W Boczonadi Veronika V Poulton Joanna J Pyle Angela A Calabrese Claudia C Gomez-Duran Aurora A Schara Ulrike U Pitceathly Robert D S RDS Hanna Michael G MG Joost Kairit K Cotta Ana A Paim Julia Filardi JF Navarro Monica Machado MM Duff Jennifer J Mattman Andre A Chapman Kristine K Servidei Serenella S Della Marina Adela A Uusimaa Johanna J Roos Andreas A Mootha Vamsi V Hirano Michio M Tulinius Mar M Giri Mamta M Hoffmann Eric P EP Lochmüller Hanns H DiMauro Salvatore S Minczuk Michal M Chinnery Patrick F PF Müller Juliane S JS Horvath Rita R

The EMBO journal 20201031 23

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 EARS ...[more]

PMID: 33128823

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Dataset Information

Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency

Publications

Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency.

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