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Molecular and Cellular Biology, August 2006, p. 5675-5687, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00112-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Role of Human Mitochondrial Nfs1 in Cytosolic Iron-Sulfur Protein Biogenesis and Iron Regulation

Annette Biederbick,1,§ Oliver Stehling,1,§ Ralf Rösser,1 Brigitte Niggemeyer,1 Yumi Nakai,2 Hans-Peter Elsässer,1 and Roland Lill1*

Institut für Zytobiologie, Philipps Universität Marburg, Robert-Koch-Str. 6, 35037 Marburg, Germany,1 Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Japan2

Received 18 January 2006/ Returned for modification 15 February 2006/ Accepted 19 May 2006

The biogenesis of iron-sulfur (Fe/S) proteins in eukaryotes is a complex process involving more than 20 components. So far, functional investigations have mainly been performed in Saccharomyces cerevisiae. Here, we have analyzed the role of the human cysteine desulfurase Nfs1 (huNfs1), which serves as a sulfur donor in biogenesis. The protein is located predominantly in mitochondria, but small amounts are present in the cytosol/nucleus. huNfs1 was depleted efficiently in HeLa cells by a small interfering RNA (siRNA) approach, resulting in a drastic growth retardation and striking morphological changes of mitochondria. The activities of both mitochondrial and cytosolic Fe/S proteins were strongly impaired, demonstrating that huNfs1 performs an essential function in Fe/S protein biogenesis in human cells. Expression of murine Nfs1 (muNfs1) in huNfs1-depleted cells restored both growth and Fe/S protein activities to wild-type levels, indicating the specificity of the siRNA depletion approach. No complementation of the growth retardation was observed, when muNfs1 was synthesized without its mitochondrial presequence. This extramitochondrial muNfs1 did not support maintenance of Fe/S protein activities, neither in the cytosol nor in mitochondria. In conclusion, our study shows that the essential huNfs1 is required inside mitochondria for efficient maturation of cellular Fe/S proteins. The results have implications for the regulation of iron homeostasis by cytosolic iron regulatory protein 1.

* Corresponding author. Mailing address: Institut für Zytobiologie, Philipps Universität Marburg, Robert-Koch-Str. 6, 35037 Marburg, Germany. Phone: 49 6421 286 6449. Fax: 49 6421 286 6414. E-mail: lill{at}staff.uni-marburg.de.

§ These authors contributed equally to the work.

Molecular and Cellular Biology, August 2006, p. 5675-5687, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00112-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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