University of Oulu

The EMBO Journal (2020) 39: e105364, https://doi.org/10.15252/embj.2020105364

Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency

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Author: Hathazi, Denisa1; Griffin, Helen2; Jennings, Matthew J.1;
Organizations: 1Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK
2Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
3MRC Mitochondrial Biology Unit, Cambridge, UK
4Karolinska Institute, University of Stockholm, Stockholm, Sweden
5Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Oxford, UK
6Pediatric Neurology, University of Essen, Essen, Germany
7Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK
8Centre of Allergology and Immunology, East‐Tallinn Central Hospital, Tallinn, Estonia
9Department of Pathology, Neuromuscular Unit, SARAH Network of Rehabilitation Hospitals, Belo Horizonte, Brazil
10Department of Pediatrics, Neuromuscular Unit, SARAH Network of Rehabilitation Hospitals, Belo Horizonte, Brazil
11Department of Pathology and Laboratory Medicine SPH, St. Paul's Hospital, Vancouver, BC, Canada
12Department of Neurology, Università Cattolica del Sacro Cuore, Roma, Italy
13PEDEGO Research Unit/Pediatric Neurology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
14Leibniz Institute for Analytical Sciences (ISAS), Dortmund, Germany
15Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA
16Department of Neurology, Columbia University Medical Center, New York, NY, USA
17Department of Pediatrics, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
18School of Pharmacy and Pharmaceutical Sciences, Binghampton University, New York, NY, USA
19Department of Neuropediatrics and Muscle Disorders, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
20Centro Nacional de Análisis Genómico (CNAG‐CRG), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
21Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
22Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.7 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe202101222504
Language: English
Published: EMBO Press, 2020
Publish Date: 2021-01-22
Description:

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.

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Series: EMBO journal
ISSN: 0261-4189
ISSN-E: 1460-2075
ISSN-L: 0261-4189
Volume: 39
Issue: 23
Article number: e105364
DOI: 10.15252/embj.2020105364
OADOI: https://oadoi.org/10.15252/embj.2020105364
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
3111 Biomedicine
Subjects:
Funding: RH was supported by the European Research Council [309548], the Wellcome Investigator Award [109915/Z/15/Z]. the Medical Research Council (UK) [MR/N025431/1]; the Wellcome Trust Pathfinder Scheme [201064/Z/16/Z], the Newton Fund [UK/Turkey, MR/N027302/1], the Lily Foundation and the Evelyn Trust. PFC is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), the Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease, the Evelyn Trust, and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. DH and AR gratefully acknowledge the financial support by the Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein‐Westfalen and the Bundesministerium für Bildung und Forschung. This work was also supported by a grant of the French Muscular Dystrophy Association (AFM‐Téléthon; #21466) to AR. HL received funding from the Canadian Institute of Health and Research (CIHR FDN‐167281). RDSP is supported by a Medical Research Council Clinician Scientist Fellowship (MR/S002065/1). Part of this work was undertaken in the UCLH/UCL Queen Square Institute of Neurology sequencing facility, which received a proportion of funding from the Department of Health's NIHR BRC funding scheme. The clinical and diagnostic “Rare Mitochondrial Disorders” Service in London is funded by the UK NHS Highly Specialised Commissioners.
Copyright information: © 2020 The Authors Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
  https://creativecommons.org/licenses/by/4.0/