NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4(-/-) mice and Leigh syndrome patients: A stabilizing role for NDUFAF2
| Autor: | Leo G.J. Nijtmans, Mariël A.M. van den Brand, Jori A. L. Wagenaars, Leonid A. Sazanov, Werner J.H. Koopman, Jan A.M. Smeitink, Merel J. W. Adjobo-Hermans, Sjenet E. van Emst-de Vries, Mariusz R. Wieckowski, Richard J. Rodenburg, Peter H.G.M. Willems, Aleksandra Wojtala, Ria de Haas |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
NDUFA12 Mutation NDUFS7 Chemistry NDUFS1 Protein subunit Biophysics NDUFS4 Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] NDUFV1 Cell Biology Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] medicine.disease_cause Biochemistry Molecular biology 03 medical and health sciences All institutes and research themes of the Radboud University Medical Center 030104 developmental biology 0302 clinical medicine medicine Inner mitochondrial membrane 030217 neurology & neurosurgery |
| Zdroj: | Biochimica et Biophysica Acta. Bioenergetics, 1861 Biochimica et Biophysica Acta. Bioenergetics, 1861, 8 |
| ISSN: | 0005-2728 |
| Popis: | Mutations in NDUFS4, which encodes an accessory subunit of mitochondrial oxidative phosphorylation (OXPHOS) complex I (CI), induce Leigh syndrome (LS). LS is a poorly understood pediatric disorder featuring brain-specific anomalies and early death. To study the LS pathomechanism, we here compared OXPHOS proteomes between various Ndufs4-/- mouse tissues. Ndufs4-/- animals displayed significantly lower CI subunit levels in brain/diaphragm relative to other tissues (liver/heart/kidney/skeletal muscle), whereas other OXPHOS subunit levels were not reduced. Absence of NDUFS4 induced near complete absence of the NDUFA12 accessory subunit, a 50% reduction in other CI subunit levels, and an increase in specific CI assembly factors. Among the latter, NDUFAF2 was most highly increased. Regarding NDUFS4, NDUFA12 and NDUFAF2, identical results were obtained in Ndufs4-/- mouse embryonic fibroblasts (MEFs) and NDUFS4-mutated LS patient cells. Ndufs4-/- MEFs contained active CI in situ but blue-native-PAGE highlighted that NDUFAF2 attached to an inactive CI subcomplex (CI-830) and inactive assemblies of higher MW. In NDUFA12-mutated LS patient cells, NDUFA12 absence did not reduce NDUFS4 levels but triggered NDUFAF2 association to active CI. BN-PAGE revealed no such association in LS patient fibroblasts with mutations in other CI subunit-encoding genes where NDUFAF2 was attached to CI-830 (NDUFS1, NDUFV1 mutation) or not detected (NDUFS7 mutation). Supported by enzymological and CI in silico structural analysis, we conclude that absence of NDUFS4 induces near complete absence of NDUFA12 but not vice versa, and that NDUFAF2 stabilizes active CI in Ndufs4-/- mice and LS patient cells, perhaps in concert with mitochondrial inner membrane lipids. |
| Databáze: | OpenAIRE |
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