biostudies-literatureBeilschmidt LKEuropean Research Council15124https://www.ebi.ac.uk/biostudies/studies/S-EPMC5437272biostudies-literatureUnknown8Mammalian A-type proteins, ISCA1 and ISCA2, are evolutionarily conserved proteins involved in iron-sulfur cluster (Fe-S) biogenesis. Recently, it was shown that ISCA1 and ISCA2 form a heterocomplex that is implicated in the maturation of mitochondrial Fe₄S₄ proteins. Here we report that mouse ISCA1 and ISCA2 are Fe₂S₂-containing proteins that combine all features of Fe-S carrier proteins. We use biochemical, spectroscopic and in vivo approaches to demonstrate that despite forming a complex, ISCA1 and ISCA2 establish discrete interactions with components of the late Fe-S machinery. Surprisingly, knockdown experiments in mouse skeletal muscle and in primary cultures of neurons suggest that ISCA1, but not ISCA2, is required for mitochondrial Fe<sub>Nature communicationsISCA1 is essential for mitochondrial Fe₄S₄ biogenesis in vivo.PMC5437272206634Martelli AKoebel PFournier MWeiss AClemancey MBeilschmidt LKSanakis IPuccio HHograindleur MABlondin GMessaddeq NOllagnier de Choudens SEisenmann ASchmucker SfalseISCA1 is essential for mitochondrial Fe₄S₄ biogenesis in vivo.Mammalian A-type proteins, ISCA1 and ISCA2, are evolutionarily conserved proteins involved in iron-sulfur cluster (Fe-S) biogenesis. Recently, it was shown that ISCA1 and ISCA2 form a heterocomplex that is implicated in the maturation of mitochondrial Fe₄S₄ proteins. Here we report that mouse ISCA1 and ISCA2 are Fe₂S₂-containing proteins that combine all features of Fe-S carrier proteins. We use biochemical, spectroscopic and in vivo approaches to demonstrate that despite forming a complex, ISCA1 and ISCA2 establish discrete interactions with components of the late Fe-S machinery. Surprisingly, knockdown experiments in mouse skeletal muscle and in primary cultures of neurons suggest that ISCA1, but not ISCA2, is required for mitochondrial Fe<sub>2017-01-01T00:00:00Z2017 May2026-05-04T15:30:55.273Z2019-03-27T02:45:24ZS-EPMC54372722849223310.1038/ncomms15124