Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency
Abstract: Reversible infantile respiratory chain deficiency (RIRCD) is a raremitochondrial myopathy leading to severe metabolic disturbancesin infants, which recover spontaneously after 6-months of age.RIRCD is associated with the homoplasmic m.14674T>C mitochon-drial DNA mutation; however, only ~ 1/100 carriers develop thedisease. We studied 27 affected and 15 unaffected individuals from19 families and found additional heterozygous mutations in nucleargenes interacting with mt-tRNAGlu including EARS2 and TRMU inthe majority of affected individuals, but not in healthy carriers ofm.14674T>C, supporting a digenic inheritance. Our transcriptomicand proteomic analysis of patient muscle suggests a stepwise mech-anism where first, the integrated stress response associated withincreased FGF21 and GDF15 expression enhances the metabolismmodulated by serine biosynthesis, one carbon metabolism, TCA lipidoxidation and amino acid availability, while in the second stepmTOR activation leads to increased mitochondrial biogenesis. Ourdata suggest that the spontaneous recovery in infants with digenicmutations may be modulated by the above described changes. Simi-lar mechanisms may explain the variable penetrance and tissuespecificity of other mtDNA mutations and highlight the potentialrole of amino acids in improving mitochondrial disease
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Anmerkungen
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EMBO Journal. - 39, 23 (2020) , e105364, ISSN: 1460-2075
- Ereignis
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Veröffentlichung
- (wo)
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Freiburg
- (wer)
-
Universität
- (wann)
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2020
- Urheber
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Hathazi, Denisa
Griffin, Helen
Jennings, Matthew J.
Giunta, Michele
Lochmüller, Hanns
Müller, Juliane S.
Horvath, Rita
- DOI
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10.15252/embj.2020105364
- URN
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urn:nbn:de:bsz:25-freidok-1694436
- Rechteinformation
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Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
-
25.03.2025, 13:53 MEZ
Datenpartner
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Beteiligte
- Hathazi, Denisa
- Griffin, Helen
- Jennings, Matthew J.
- Giunta, Michele
- Lochmüller, Hanns
- Müller, Juliane S.
- Horvath, Rita
- Universität
Entstanden
- 2020
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