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dc.contributor.authorTerburgh, Karin
dc.contributor.authorLindeque, Zander
dc.contributor.authorMason, Shayne
dc.contributor.authorVan der Westhuizen, Francois
dc.contributor.authorLouw, Roan
dc.date.accessioned2019-03-08T12:51:40Z
dc.date.available2019-03-08T12:51:40Z
dc.date.issued2019
dc.identifier.citationTerburgh, K. et al. 2019. Metabolomics of Ndufs4−/− skeletal muscle: adaptive mechanisms converge at the ubiquinone-cycle, Biochimica et biophysica acta: molecular basis of disease, 1865(1):98-106. [https://doi.org/10.1016/j.bbadis.2018.10.034]en_US
dc.identifier.issn0925-4439
dc.identifier.issn0006-3002 (Online)
dc.identifier.urihttp://hdl.handle.net/10394/31931
dc.identifier.urihttps://www.sciencedirect.com/science/article/pii/S092544391830437X
dc.identifier.urihttps://doi.org/10.1016/j.bbadis.2018.10.034
dc.description.abstractLeigh syndrome is one of the most common childhood-onset neurometabolic disorders resulting from a primary oxidative phosphorylation dysfunction and affecting mostly brain tissues. Ndufs4−/− mice have been widely used to study the neurological responses in this syndrome, however the reason why these animals do not display strong muscle involvement remains elusive. We combined biochemical strategies and multi-platform metabolomics to gain insight into the metabolism of both glycolytic (white quadriceps) and oxidative (soleus) skeletal muscles from Ndufs4−/− mice. Enzyme assays confirmed severely reduced (80%) CI activity in both Ndufs4−/− muscle types, compared to WTs. No significant alterations were evident in other respiratory chain enzyme activities; however, Ndufs4−/− solei displayed moderate decreases in citrate synthase (12%) and CIII (18%) activities. Through hypothesis-generating metabolic profiling, we provide the first evidence of adaptive responses to CI dysfunction involving non-classical pathways fueling the ubiquinone (Q) cycle. We report a respective 48 and 34 discriminatory metabolites between Ndufs4−/− and WT white quadriceps and soleus muscles, among which the most prominent alterations indicate the involvement of the glycerol-3-phosphate shuttle, electron transfer flavoprotein system, CII, and proline cycle in fueling the Q cycle. By restoring the electron flux to CIII via the Q cycle, these adaptive mechanisms could maintain adequate oxidative ATP production, despite CI deficiency. Taken together, our results shed light on the underlying pathogenic mechanisms of CI dysfunction in skeletal muscle. Upon further investigation, these pathways could provide novel targets for therapeutic intervention in CI deficiency and potentially lead to the development of new treatment strategiesen_US
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.subjectDufs4 knockout miceen_US
dc.subjectSkeletal muscleen_US
dc.subjectMetabolomicsen_US
dc.subjectMitochondrial diseaseen_US
dc.subjectComplex I deficiencyen_US
dc.subjectUbiquinone-cycleen_US
dc.titleMetabolomics of Ndufs4−/− skeletal muscle: adaptive mechanisms converge at the ubiquinone-cycleen_US
dc.typeArticleen_US
dc.contributor.researchID12662275 - Lindeque, Jeremie Zander
dc.contributor.researchID10986707 - Louw, Roan
dc.contributor.researchID10213503 - Van der Westhuizen, Francois Hendrikus
dc.contributor.researchID21487855 - Mason, Shayne William
dc.contributor.researchID23475684 - Terburgh, Karin


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