Table 1. Currently known diseases caused by mutations in genes related to mammalian mitochondrial iron–sulfur cluster biosynthesis and transfer.

Protein	Functions	Associated diseases	Causes	Reference
Mitochondrial Fe–S biosynthesis associated genes
Nfs1	Cysteine desulfurase, supplies inorganic sulfur to Fe–S clusters	Infantile complex II/III deficiency (IMC23D)	Missense mutation c.251G>A, p.Arg72Gln	Farhan et al. 2014; Land and Rouault 1998
ISD11	Binds cysteine desulfurase and helps free inorganic sulfur for Fe–S clusters.	Combined oxidative phosphorylation defects 19	Missense mutation c.203G>T, p.R68L	Adam et al. 2006; Lim et al. 2013
ACP	Interacts with ISD11 and stabilizes the function of NSF1 and the biosynthesis of Fe–S	Manic depressive illness (Bipolar disorder)	(SNP association)	Wellcome Trust Case Control 2007
Frataxin (FXN)	Involves Fe–S biosynthesis	Friedreich's ataxia (FRDA)	GAA trinucleotide repeat expansion in intron 1, suppresses the transcription of FXN and reduces its expression	Campuzano et al. 1996; Gellera et al. 2007
ISCU	Scaffold for Fe–S	Myopathy with lactic acidosis	Splicing mistake or splicing mistake and missense mutation c.149G> A, p.G50E	Kollberg et al. 2009; Mochel et al. 2008; Tong and Rouault 2006
FDX1	Electron transport intermediate for mitochondrial cytochromes P450 and Fe–S biosynthesis	–	–	Okamura et al. 1985; Shi et al. 2012
FDX2	Transfers electrons from NADPH to Fe–S biosynthesis via FDXR	Mitochondrial myopathy, episodic, with or without optic atrophy and reversible leukoencephalopathy (MEOAL)	Homozygote mutation c.1A>T, p.M1L or c.431C>T, p.P144L	Gurgel-Giannetti et al. 2018; Sheftel et al. 2010; Spiegel et al. 2014
FDXR	Receives electrons from NADPH, thus initiating the electron-transport chain serving mitochondrial cytochromes P450 and Fe–S biosynthesis	Auditory neuropathy and optic atrophy (ANOA)	Homozygote mutation c.916C>T, Arg306Cys or heterozygote mutation Gln419Ter/Leu215Val/Glu477Lys	Lin et al. 1990; Paul et al. 2017; Solish et al. 1988
Mitochondrial Fe–S transport associated genes
HSPA9	Chaperone. It involves Fe–S transport	Congenital Sideroblastic anemia 4	Gene deletion	Kaul et al. 1995; Schmitz-Abe et al. 2015
		EVEN-PLUS syndrome	Homozygote mutation c.376C>T, p.R126W	Royer-Bertrand et al. 2015
HSC20	Cochaperone. It binds target proteins that contain the LYR motif	Congenital sideroblastic anemias (CSAs)	A paternally-inherited promoter variant (c.-134C>A) predicted to disrupt a conserved ETS transcription factor binding site, and a maternally-inherited frameshift (c.259dup, p.T87fs*27).	Maio et al. 2014; Sun et al. 2003; Uhrigshardt et al. 2010；Crispin et al. 2017
GLRX5	Fe–S carrier protein	Sideroblastic anemia 3	Mistaken splicing leads to low expression of GLXR5	Camaschella et al. 2007; Wingert et al. 2005
NFU1	Fe–S delivery to specific recipients	Multiple mitochondrial dysfunctions syndrome 1 (MMDS1)	c.545G>A,p.Arg182Gln; or homozygote mutation c.622G>T (p.Gly208Cys)	Al-Hassnan et al. 2015; Lorain et al. 2001; Navarro-Sastre et al. 2011
BOLA3	Fe–S delivery to specific recipients	Multiple mitochondrial dysfunctions syndrome 2 (MMDS2)	Single base-pair duplication c.123dupA, in exon 2, causing a frameshift that produces a premature stop codon; or homozygote missense mutation c.200T>A in exon 3, p.167N	Haack et al. 2013; Seyda et al. 2001; Zhou et al. 2008
IBA57	[Fe4-S4] assembly component for a subset of recipients	Multiple mitochondrial dysfunctions syndrome 3 (MMDS3)	Homozygote mutation c.941A>C,p.Gln314Pro	Ajit Bolar et al. 2013; Nilsson et al. 2009
		Autosomal recessive spastic paraplegia 74	Homozygote mutation c.678A-G	Lossos et al. 2015
ISCA2	Involves the maturation and assembly of Fe–S	Multiple mitochondrial dysfunctions syndrome 4 (MMDS4)	Homozygote mutation c.229G>A,p.G77S	Al-Hassnan et al. 2015; Sheftel et al. 2012
ISCA1	Involves the biosynthesis and assembly of Fe–S	Multiple mitochondrial dysfunctions syndrome 5 (MMDS5)	Homozygote mutation c.259G>A,p.E87K	Cozar-Castellano et al. 2004; Shukla et al. 2017
IND1	Mitochondrial translation; complex I assembly	Childhood-onset mitochondrial encephalopathy and complex I deficiency	c.166G>, p.G56R with deletion spanning exons 1-4. A second substitution in intron 9 (c.815-27T> C) resulting in aberrant splicing	Calvo et al. 2010; Sheftel et al. 2009
ABCB7	Component of the mitochondrial export machinery	X-linked sideroblastic anemia with cerebellar ataxia (XLSA/A)	Several mutations close to or in transmembrane domains of the ABC transporter	Allikmets et al. 1999; Bekri et al. 2000; Savary et al. 1997