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Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40 Page 405

The second step, newly synthesized 2Fe/2S cluster, is trafficked to the late-acting iron-sulfur machinery for
4Fe/4S cluster synthesis and mitochondrial export. How the Hsp70 chaperone system shuttles the 2Fe/2S
complex from early to the late acting iron-sulfur synthesis complex is not well understood in higher order
eukaryotes. The chaperone complex, consisting of the proteins GRP75, HSPA9, HSCB, GRPEL1/2, and
GLRX5, extracts the 2Fe/2S complex and transfers the complex to glutaredoxin Grx5. Recessive mutations
in GLRX5 induce nonketotic hyperglycinemia with neurodegeneration, leukoencephalopathy, optic
atrophy, and spastic paraplegia in childhood [206] .

The final maturation of the 2Fe/2S complex into the 4Fe/4S complex occurs in the complex containing
[49]
the mammalian A-type proteins ISCA1 and ISCA2, and the folate binding protein IBA57 . Due to the
downstream delivery proteins, deficiency of any constituent of this maturation or late-acting complex
results in loss of functional ETC and lipoic acid. Delivery proteins, Nfu1, BOL1, and BOLA3, are then
used to specifically target 4Fe/4S clusters to the proper apoprotein. Recessive variants in the genes of the
late maturation of 4Fe/4S complex and dysfunctional delivery proteins give rise to the group of multiple
mitochondrial dysfunction syndromes (MMDS). There are five different MMDS encoded by NFU1
(MMDS1), BOLA3 (MMDS2), IBA57 (MMDS3), ISCA2 (MMDS4), and ISCA1 (MMDS5). Clinically, these
diseases are characterized by infantile encephalopathy, non-ketotic hyperglycemia, myopathy, early death,
and leukoencephalopathy [206-208,241] . In animals, models of cardiac hypertrophy are produced by ABCB7
transporter variants, an iron transport membrane protein that alters Complex IV and V function and
contributes to heart failure [242] . However, human studies or patients have not been described.

Neurodegeneration with brain iron accumulation (NBIA) are a group of neurodegenerative diseases
characterized by progressive central nervous system dysfunction and iron accumulation. To date, there
are 10 candidate genes that have been identified with four located within mitochondria, PANK2, COASY,
PLA2G6, and C190rf12. Pantothenate kinase 2 encoded by PANK2 is located within the intermembrane
space and phosphorylates vitamin B5 in the first reaction of the CoA biosynthetic pathway. Iron
accumulation occurs in the globus pallidus, substantia nigra pars reticularis, cerebellar white matter,
nucleus gracilis, and dentate nucleus [243] . Disease onset is usually young childhood and presents with a
progressive dystonia, rigidity, dysarthria, and spasticity. C19orf12 encodes a mitochondrial membrane
protein of unknown function. Variants in C19orf12 induce a progressive spastic paraplegia, optic atrophy,
motor axonal neuropathy, and psychiatric problems and has been named mitochondrial membrane
protein-associated neurodegeneration [244,245] . Age of onset can vary from childhood to well into adulthood,
and both autosomal recessive and dominant types have been described [244,245] . Variants in COASY lead
to an early-onset autosomal recessive form of NIBA, which has been named COASY protein-associated
neurodegeneration. The COASY protein is found mostly in the matrix, but also has been identified on
the outer membrane and catalyzes the final steps of CoA biosynthesis [246] . Variants induce a mild oro-
mandibular dystonia with dysarthria, spastic-dystonic gait, severe Parkinsonism, areflexia, and eventual
loss of gait. The solute carrier, SLC25A42 is thought to transfer CoA into the mitochondrial matrix.
Recently variants in SLC24A42 have been associated with developmental delay, epilepsy, dystonia, and
basal ganglia lesions [247] . Another iron related protein, iPLA2, is encoded by PLA2G6 and is a calcium-
independent phospholipase A2 group VI that releases free fatty acids and lysophospholipids from
glycerophospholipids [248] . iPLA2 is localized to the mitochondria and cytoplasm. Loss of iPLA2 activity
has been associated with increased mitochondrial lipid peroxidation, loss of membrane potential, and
decreased ATP synthesis and abnormal organelle morphology [249] . Recessive mutations cause three different
but overlapping phenotypes: classic infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy,
and PLA2G6-related dystonia-Parkinsonism. The exact mechanism of mitochondrial involvement is not
completely understood. Phenotypically, mutations cause a cerebellar ataxia, psychomotor regression,
neuroaxonal dystrophy, dystonia, and Parkinsonism [250] .