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

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

Content Provider	PubMed Central
Author	Gorman, Grainne S. Blakely, Emma L. Hornig-do, Hue-tran Tuppen, Helen A. L. Greaves, Laura C. He, Langping Baker, Angela Falkous, Gavin Newman, Jane Trenell, Michael I. Lecky, Bryan Petty, Richard K. Turnbull, Doug M. Mcfarland, Robert Taylor, Robert W.
Copyright Year	2015
Abstract	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.
Related Links	http://dx.doi.org/10.1042/cs20140705
Ending Page	904
Page Count	10
Starting Page	895
File Format	PDF
ISSN	01435221
e-ISSN	14708736
Journal	Clinical Science (London, England : 1979)
Issue Number	12
Volume Number	128
Language	English
Publisher	Portland Press Ltd.
Publisher Date	2015-06-01
Access Restriction	Open
Rights Holder	Portland Press Ltd.
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine

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