Iron Regulatory Protein 1 Sustains Mitochondrial Iron Loading and Function in Frataxin Deficiency

• Published in: Cell metabolism Vol. 21; no. 2; pp. 311 - 323
• Main Authors: Martelli, Alain, Schmucker, Stéphane, Reutenauer, Laurence, Mathieu, Jacques R.R., Peyssonnaux, Carole, Karim, Zoubida, Puy, Hervé, Galy, Bruno, Hentze, Matthias W., Puccio, Hélène
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.02.2015
• Subjects: Animals; Frataxin; Friedreich Ataxia - genetics; Friedreich Ataxia - metabolism; Friedreich Ataxia - pathology; Iron - metabolism; Iron Regulatory Protein 1 - deficiency; Iron Regulatory Protein 1 - genetics; Iron Regulatory Protein 1 - metabolism; Iron-Binding Proteins - genetics; Iron-Binding Proteins - metabolism; Iron-Sulfur Proteins - deficiency; Iron-Sulfur Proteins - metabolism; Liver - metabolism; Liver - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - metabolism
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2015.01.010

Mitochondrial iron accumulation is a hallmark of diseases associated with impaired iron-sulfur cluster (Fe-S) biogenesis, such as Friedreich ataxia linked to frataxin (FXN) deficiency. The pathophysiological relevance of the mitochondrial iron loading and the underlying mechanisms are unknown. Using a mouse model of hepatic FXN deficiency in combination with mice deficient for iron regulatory protein 1 (IRP1), a key regulator of cellular iron metabolism, we show that IRP1 activation in conditions of Fe-S deficiency increases the available cytosolic labile iron pool. Surprisingly, our data indicate that IRP1 activation sustains mitochondrial iron supply and function rather than driving detrimental iron overload. Mitochondrial iron accumulation is shown to depend on mitochondrial dysfunction and heme-dependent upregulation of the mitochondrial iron importer mitoferrin-2. Our results uncover an unexpected protective role of IRP1 in pathological conditions associated with altered Fe-S metabolism. [Display omitted] •Activation of IRP1 upon frataxin deficiency increases iron import and availability•IRP1 secures mitochondrial iron needs and function under Fe-S cluster deficit•IRP1 sustains mitochondrial iron overload mediated by mitoferrin-2 upregulation•IRP1 has a protective role in pathological condition Mitochondrial iron accumulation is a hallmark of impaired Fe-S cluster biogenesis in Friedreich ataxia, linked to frataxin deficiency. Martelli et al. show that IRP1 activation in conditions of Fe-S deficiency increases the available cytosolic labile iron pool. Surprisingly, this mechanism has a mitochondrial protective role.