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Novel MTND1 mutations cause isolated exercise intolerance, complex I deficiency and increased assembly factor expression

Lookup NU author(s): Professor Grainne Gorman, Dr Hue Hornig - Do, Dr Helen Tuppen, Dr Laura Greaves, Dr Langping He, Angela Baker, Gavin Falkous, Jane Newman, Professor Mike TrenellORCiD, Emeritus Professor Doug Turnbull, Professor Bobby McFarlandORCiD, Professor Robert Taylor



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


Complex I (CI) is the largest of the five multi-subunit complexes constituting the human oxidative phosphorylation (OXPHOS) system. Seven of its catalytic core subunits are encoded by mitochondrial DNA (ND (NADH dehydrogenase) 1-6, ND4L (NADH dehydrogenase subunit 4L)), with mutations in all seven having been reported in association with isolated CI deficiency. We investigated two unrelated adult patients presenting with marked exercise intolerance, persistent lactic acidaemia and severe muscle-restricted isolated CI deficiency associated with sub-sarcolemmal mitochondrial accumulation. Screening of the mitochondrial genome detected novel mutations in the MTND1 (NADH dehydrogenase subunit 1) gene, encoding subunit of CI [ Patient 1, m.3365T>C predicting p.(Leu20Pro); Patient 2, m.4175G>A predicting p.(Trp290*)] at high levels of mitochondrial DNA heteroplasmy in skeletal muscle. We evaluated the effect of these novel MTND1 mutations on complex assembly showing that CI assembly, although markedly reduced, was viable in the absence of detectable ND1 signal. Real-time PCR and Western blotting showed overexpression of different CI assembly factor transcripts and proteins in patient tissue. Together, our data indicate that the mechanism underlying the expression of the biochemical defect may involve a compensatory response to the novel MTND1 gene mutations, promoting assembly factor up-regulation and stabilization of respiratory chain super-complexes, resulting in partial rescue of the clinical phenotype.

Publication metadata

Author(s): Gorman GS, Blakely EL, Hornig-Do HT, Tuppen HAL, Greaves LC, He LP, Baker A, Falkous G, Newman J, Trenell MI, Lecky B, Petty RK, Turnbull DM, McFarland R, Taylor RW

Publication type: Article

Publication status: Published

Journal: Clinical Science

Year: 2015

Volume: 128

Issue: 12

Pages: 895-904

Print publication date: 01/06/2015

Online publication date: 27/01/2015

Acceptance date: 27/01/2015

Date deposited: 13/08/2015

ISSN (print): 0143-5221

ISSN (electronic): 1470-8736

Publisher: Portland Press Ltd


DOI: 10.1042/CS20140705


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Funder referenceFunder name
North Tyneside Comprehensive Local Research Network
U.K. National Institute for Health Research (NIHR) Biomedical Research Centre for Ageing and Age-Related Diseases
Deutsche Forschungsgemeinschaft
Newcastle NIHR Biomedical Research Centre
U.K. NHS Highly Specialized Rare Mitochondrial Disease of Adults and Children Service
U.K. Senior Fellowship
0800674Medical Research Council
096919Z/11/ZWellcome Trust
M501700Medical Research Council
096919/Z/11/ZWellcome Trust