PXD020181

PXD020181 is an original dataset announced via ProteomeXchange.

Title	Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency
Description	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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:13:14.666.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Denisa Hathazi
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-07-03 03:59:43	ID requested
1	2020-10-12 23:11:32	announced
2	2020-11-05 02:07:13	announced	2020-11-05: Updated publication reference for PubMed record(s): 33128823.
⏵ 3	2024-10-22 05:13:15	announced	2024-10-22: Updated project metadata.

10.15252/embj.2020105364;

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, Mattman A, Chapman K, Servidei S, Della Marina A, Uusimaa J, Roos A, Mootha V, Hirano M, Tulinius M, Giri M, Hoffmann EP, Lochm, ü, ller H, DiMauro S, Minczuk M, Chinnery PF, M, ü, ller JS, Horvath R, Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency. EMBO J, 39(23):e105364(2020) [pubmed]

submitter keyword: mitochondrial myopathy, digenic inheritance, reversible infantile respiratory chain deficiency, homoplasmic tRNA mutation

Rita Horvath
contact affiliation	Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK
contact email	rh732@medschl.cam.ac.uk
lab head
Denisa Hathazi
contact affiliation	University of Cambridge, Department of Clinical Neurosciences, School of Clinical Medicine
contact email	gdh29@cam.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/10/PXD020181

PRIDE project URI

• PRIDE
  1. PXD020181
     1. Label: PRIDE project
     2. Name: Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency