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First published online 9 August 2005
doi: 10.1242/jcs.02516

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Extra-mitochondrial localisation of frataxin and its association with IscU1 during enterocyte-like differentiation of the human colon adenocarcinoma cell line Caco-2

¹ Dipartimento di Biologia e Patologia Cellulare e Molecolare, Via S. Pansini 5, Istituto di Endocrinologia ed Oncologia Sperimentale Centro Nazionale delle Ricerche, Università `Federico II', Napoli, Italy
² Unità Operativa Complessa di Anatomia Patologica, Istituto Nazionale Tumori, Via M. Semmola, 80131 Napoli, Italy
³ Unità Operativa Complessa di Oncologia Medica B, Istituto Nazionale Tumori, Via M. Semmola, 80131 Napoli, Italy

^* Author for correspondence (e-mail: angacqua{at}unina.it)

Accepted 28 May 2005

Friedreich's ataxia is a recessive neurodegenerative disease due to insufficient expression of the mitochondrial protein frataxin. Although it has been shown that frataxin is involved in the control of intracellular iron metabolism, by interfering with the mitochondrial biosynthesis of proteins with iron/sulphur (Fe/S) clusters its role has not been well established. We studied frataxin protein and mRNA expression and localisation during cellular differentiation. We used the human colon adenocarcinoma cell line Caco-2, as it is considered a good model for intestinal epithelial differentiation and the study of intestinal iron metabolism. Here we report that the protein, but not the mRNA frataxin levels, increase during the enterocyte-like differentiation of Caco-2 cells, as well as in in-vivo-differentiated enterocytes at the upper half of the crypt-villus axis. Furthermore, subcellular fractionation and double immunostaining, followed by confocal analysis, reveal that frataxin localisation changes during Caco-2 cell differentiation. In particular, we found an extramitochondrial localisation of frataxin in differentiated cells. Finally, we demonstrate a physical interaction between extramitochondrial frataxin and IscU1, a cytoplasmic isoform of the human Fe/S cluster assembly machinery. Based on our data, we postulate that frataxin could be involved in the biosynthesis of iron-sulphur proteins not only within the mitochondria, but also in the extramitochondrial compartment. These findings might be of relevance for the understanding of both the pathogenesis of Friedreich's ataxia and the basic mechanism of Fe/S cluster biosynthesis.

Key words: Frataxin, Caco-2 cells, Differentiation, Mitochondrial mass, Subcellular localisation

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