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Complex I (NADH:ubiquinone oxidoreductase) is the largest multiprotein enzyme of the oxidative phosphorylation system. Its assembly in human cells is poorly understood and no proteins assisting this process have yet been described. A good candidate is NDUFAF1, the human homologue of Neurospora crassacomplex I chaperone CIA30. Here, we demonstrate that NDUFAF1 is a mitochondrial protein that is involved in the complex I assembly process. | ềFEBS Journal Human mitochondrial complex I assembly is mediated by NDUFAF1 Rutger O. Vogel1 z Rolf J. R. J. Janssen1 z Cristina Ugalde1 2 Melissa Grovenstein1 Richard J Huijbens1 Henk-Jan Visch3 Lambert P. van den Heuvel1 Peter H. Willems3 Massimo Zeviani4 Jan A. M. Smeitink1 and Leo G. J. Nijtmans1 1 Department of Paediatrics Radboud University Nijmegen MedicalCentre the Netherlands 2 Centro de Investigacion HospitalUniversitario 12 de Octubre Madrid Spain 3 Department of Biochemistry Radboud University Nijmegen MedicalCentre the Netherlands 4 Unit of Molecular Neurogenetics NationalInstitute of Neurology C. Besta Milan Italy Keywords assembly NDUFAF1 complex I mitochondria oxidative phosphorylation Correspondence J. Smeitink Nijmegen Centre for MitochondrialDisorders Department of Paediatrics Radboud University Nijmegen MedicalCentre Geert Grooteplein 10 PO BOX 9101 6500 HB Nijmegen the Netherlands Fax 31 243616428 Tel 31 24 3614430 E-mail j.smeitink@cukz.umcn.nl Note These authors contributed equally to this work. Complex I NADH ubiquinone oxidoreductase is the largest multiprotein enzyme of the oxidative phosphorylation system. Its assembly in human cells is poorly understood and no proteins assisting this process have yet been described. A good candidate is NDUFAF1 the human homologue of Neurospora crassa complex I chaperone CIA30. Here we demonstrate that NDUFAF1 is a mitochondrial protein that is involved in the complex I assembly process. Modulating the intramitochondrial amount of NDU-FAF1 by knocking down its expression using RNA interference leads to a reduced amount and activity of complex I. NDUFAF1 is associated to two complexes of 600 and 700 kDa in size of which the relative distribution is altered in two complex I deficient patients. Analysis of NDUFAF1 expression in a conditional complex I assembly system shows that the 700 kDa complex may represent a key step in the complex I assembly process. Based on these data we propose that NDUFAF1 is an .
