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Molecular and Cellular Biology, November 2009, p. 6059-6073, Vol. 29, No. 22
0270-7306/09/$08.00+0     doi:10.1128/MCB.00817-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human Ind1, an Iron-Sulfur Cluster Assembly Factor for Respiratory Complex I{triangledown}

Alex D. Sheftel,1 Oliver Stehling,1 Antonio J. Pierik,1 Daili J. A. Netz,1 Stefan Kerscher,2 Hans-Peter Elsässer,1 Ilka Wittig,2 Janneke Balk,3 Ulrich Brandt,2 and Roland Lill1*

Institut für Zytobiologie, Philipps-Universität Marburg, Robert-Koch-Strasse 6, 35033 Marburg, Germany,1 Goethe-Universität, Zentrum der Biologischen Chemie, Molekulare Bioenergetik, Cluster of Excellence, Macromolecular Complexes, 60590 Frankfurt am Main, Germany,2 Department of Plant Sciences, University of Cambridge, Downing Street, Cambridge CB2 3EA, United Kingdom3

Received 23 June 2009/ Returned for modification 24 July 2009/ Accepted 8 September 2009

Respiratory complex I (NADH:ubiquinone oxidoreductase) is a large mitochondrial inner membrane enzyme consisting of 45 subunits and 8 iron-sulfur (Fe/S) clusters. While complex I dysfunction is the most common reason for mitochondrial diseases, the assembly of complex I and its Fe/S cofactors remains elusive. Here, we identify the human mitochondrial P-loop NTPase, designated huInd1, that is critically required for the assembly of complex I. huInd1 can bind an Fe/S cluster via a conserved CXXC motif in a labile fashion. Knockdown of huInd1 in HeLa cells by RNA interference technology led to strong decreases in complex I protein and activity levels, remodeling of respiratory supercomplexes, and alteration of mitochondrial morphology. In addition, huInd1 depletion resulted in massive decreases in several subunits (NDUFS1, NDUFV1, NDUFS3, and NDUFA13) of the peripheral arm of complex I, with the concomitant appearance of a 450-kDa subcomplex representing part of the membrane arm. By a novel radiolabeling technique, the amount of iron associated with complex I was also shown to reflect the dependence of this enzyme on huInd1 for assembly. Together, these data identify huInd1 as a new assembly factor for human respiratory complex I with a possible role in the delivery of one or more Fe/S clusters to complex I subunits.

* Corresponding author. Mailing address: Institut für Zytobiologie, Philipps-Universität Marburg, Robert-Koch-Strasse 6, 35033 Marburg, Germany. Phone: 49-6421-286 6449. Fax: 49-6421-286 6414. E-mail: Lill{at}staff.uni-marburg.de

{triangledown} Published ahead of print on 14 September 2009.

Molecular and Cellular Biology, November 2009, p. 6059-6073, Vol. 29, No. 22
0270-7306/09/$08.00+0     doi:10.1128/MCB.00817-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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