| Title: | Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency |
| Journal: | The EMBO Journal |
| Published: | 31 Oct 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/33128823/ |
| DOI: | https://doi.org/10.15252/embj.2020105364 |
| URL: | https://onlinelibrary.wiley.com/doi/pdfdirect/10.15252/embj.2020105364 |
| Citations: | 32 (12 in last 2 years) as of 8 Aug 2024 |
Publication 12897
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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.</p>
17 Keywords
- Adolescent
- Cell Line
- DNA, Mitochondrial
- Female
- Gene Expression
- Humans
- Infant
- Male
- Mitochondria
- Mitochondrial Diseases
- Mitochondrial Myopathies
- Mitochondrial Proteins
- Mutation
- Pedigree
- Proteomics
- Quadriceps Muscle
- tRNA Methyltransferases
38 Authors
- Denisa Hathazi
- Helen Griffin
- Matthew J Jennings
- Michele Giunta
- Christopher Powell
- Sarah F Pearce
- Benjamin Munro
- Wei Wei
- Veronika Boczonadi
- Joanna Poulton
- Angela Pyle
- Claudia Calabrese
- Aurora Gomez-Duran
- Ulrike Schara
- Robert D S Pitceathly
- Michael G Hanna
- Kairit Joost
- Ana Cotta
- Julia Filardi Paim
- Monica Machado Navarro
- Jennifer Duff
- Andre Mattman
- Kristine Chapman
- Serenella Servidei
- Adela Della Marina
- Johanna Uusimaa
- Andreas Roos
- Vamsi Mootha
- Michio Hirano
- Mar Tulinius
- Mamta Giri
- Eric P Hoffmann
- Hanns Lochmüller
- Salvatore DiMauro
- Michal Minczuk
- Patrick F Chinnery
- Juliane S Müller
- Rita Horvath
1 Application
| Application ID | Title |
|---|---|
| 18794 | The role of mitochondrial DNA variants in common disease |
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