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Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40 Page 409

seizures, and cognitive impairment, now known as Costeff syndrome [284] . Other ethnic groups also have
been reported. Dominant OPA3 variants demonstrate optic atrophy, cataracts, lipodystrophy, seizures, and
peripheral and autonomic neuropathy [285] .

The TMEM65 protein is located in the IMM, and, in siRNA experiments on patient fibroblasts, it altered
respiration rate and mitochondrial content [286] . The sole patient reported with biallelic TMEM65 variants
displayed microcephaly, seizures, vision loss, and global developmental delay [287] . The exact function of the
TMEM65 protein remains unknown.

Mitochondrial membrane modification/homeostasis
Phospholipids are structural components of membranes, but also physiological active within multiple
cellular processes, act as vesicles with intracellular signaling transduction and involved in mitochondrial
fusion and fission. Mitochondria contain the unique phospholipid cardiolipin, which is predominantly
found in the IMM with also a minor component of the OMM. The biophysical properties of cardiolipin
make it a non-bilayer forming acidic phospholipid fitting into the inner side of the curved IMM,
characteristic of the mitochondrial cristae. Cardiolipin is also involved in mitochondrial apoptosis and
stabilizing of ETC supercomplexes. The major site of lipid synthesis is the ER and transported via contact
points with mitochondria. Mitochondria are also intimately involved in beta-oxidation of fatty acids,
unique fatty acid synthesis, lipid cofactors, and steroid hormone production.

The X-linked gene, TAZ, encodes an acyltransferase that catalyzes the remodeling of cardiolpin [288] . In
cardiac and skeletal muscle, the predominant species of cardiolipin is reduced in favor of different acyl
composition in TAZ pathological variants. Structurally, the variants produce enlarged mitochondria with
bound glycogen, and cristae become stacked with circular arrays in heart and muscle. Phenotypically, Barth
syndrome presents dilated cardiomyopathy, prolonged QT interval, proximal myopathy, delayed motor
milestones, exercise intolerance, mild learning disabilities, delayed puberty, and neutropenia [288] .

Choline kinase beta initiated the de novo biosynthesis of phosphatidylcholine. Recessive mutations in
CHKB induce an early onset psychomotor delay, muscle weakness, and hypotonia known as megaconial
muscular dystrophy [289] . Skeletal muscle is found to have enlarged mitochondria with alteration of IMM
potential [290] .

SERAC1 is located at the contact sites between the ER and mitochondria associated membrane
and involved in the remodeling of phosphidylglycerol. Recessive mutations in SERAC1 induce
3-methylglutaconic aciduria, deafness, encephalopathy, and neuroimaging evidence of Leigh-like disease
(MEGDEL) syndrome. Disease onset is early infancy with neonatal hypoglycemia, hypotonia, hepatitis,
dystonia of hands and feet, and severe motor delay [291] .

The calcium-independent phospholipases are named group VI iPLA2s. The iPLA2s or patatin-like
phospholipases (PNPLAs) contain lipase and nucleotide-binding consensus sequences that function to
hydrolyze a free fatty acid and a lysolipid from membrane phospholipids. iPLA2 g is encoded by PNPLA8,
which is the predominant phospholipase in mammalian mitochondria [292,293] . Recessive variants in PNPLA8
give rise to microcephaly, spasticity, cerebellar and brainstem atrophy, seizures, and muscle weakness [292,293] .

The protein complement component 1 Q subcomponent-binding protein (C1QBP) is located primarily in
the matrix, with roles in inflammation, mitochondrial ribosome biogenesis, and regulation of apoptosis.
Although the precise involvement in mitochondrial function is unknown, C1QBP variants induce severely
impaired protein synthesis [294] . Patients exhibit cardiomyopathy and multisystem involvement as infants,
while those presenting later in life have a myopathy and CPEO [295] .