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A novel mechanism causing imbalance of mitochondrial fusion and fission in human myopathies

Lookup NU author(s): Marina Bartsakoulia, Dr Angela Pyle, Dr Jennifer Duff, Dr Helen GriffinORCiD, Dr Veronika Boczonadi, Professor Hanns Lochmuller, Professor Patrick Chinnery, Professor Rita HorvathORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© The Author(s) 2018. Published by Oxford University Press. All rights reserved. Mitochondrial dynamics play an important role in cellular homeostasis and a variety of human diseases are linked to its dysregulated function. Here, we describe a 15-year-old boy with a novel disease caused by altered mitochondrial dynamics. The patient was the second child of consanguineous Jewish parents. He developed progressive muscle weakness and exercise intolerance at 6 years of age. His muscle biopsy revealed mitochondrial myopathy with numerous ragged red and cytochrome c oxidase (COX) negative fibers and combined respiratory chain complex I and IV deficiency. MtDNA copy number was elevated and no deletions of the mtDNA were detected in muscle DNA. Whole exome sequencing identified a homozygous nonsense mutation (p.Q92*) in the MIEF2 gene encoding the mitochondrial dynamics protein of 49 kDa (MID49). Immunoblotting revealed increased levels of proteins promoting mitochondrial fusion (MFN2, OPA1) and decreased levels of the fission protein DRP1. Fibroblasts of the patient showed elongated mitochondria, and significantly higher frequency of fusion events, mtDNA abundance and aberrant mitochondrial cristae ultrastructure, compared with controls. Thus, our data suggest that mutations in MIEF2 result in imbalanced mitochondrial dynamics and a combined respiratory chain enzyme defect in skeletal muscle, leading to mitochondrial myopathy.

Publication metadata

Author(s): Bartsakoulia M, Pyle A, Troncoso-Chandia D, Vial-Brizzi J, Paz-Fiblas MV, Duff J, Griffin H, Boczonadi V, Lochmuller H, Kleinle S, Chinnery PF, Grunert S, Kirschner J, Eisner V, Horvath R

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2018

Volume: 27

Issue: 7

Pages: 1186-1195

Print publication date: 01/04/2018

Online publication date: 19/01/2018

Acceptance date: 16/01/2018

Date deposited: 16/04/2018

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddy033


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust