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Page 406 Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40

Lipoic acid synthase (LIAS) is a 4Fe/4S containing enzyme and interacts with S-adenosylmethione to
donate sulfur for lipoic acid formation [251] . LIAS intersects fatty acid synthesis at the formation of octanoyl-
acyl-carrier protein and three lipoate-specific steps. Octanoic acid is transferred to the glycine cleavage
H protein by LIPT2 and lipoate transfer protein LIPT1, which is necessary to donate lipoylate to the E2
subunits of the 2-oxoacid dehydrogenases. Recessive variants in LIAS result in nonketotic hyperglycinemia
with early onset seizures, cardiomyopathy, and encephalopathy [206-208] . Lipoic acid is a required cofactor
for multiple enzyme functions in the mitochondria: pyruvate dehydrogenase, alpha ketoglutarate
dehydrogenase, 2-oxoadipate dehydrogenase, branch-chain ketoacid dehydrogenase, and glycine
cleavage system. Recessive variants in LIPT1 and LIPT2 can induce a variety of clinical range of disorders
from Leigh syndrome to non-ketotic hyperglycemia, hypotonia, seizures, microcephaly, psychomotor
retardation, and cardiomyopathy [251] .

SFXN4 is one of the sideroflexin proteins, with an unknown function in mitochondria. There is data to
suggest that SFXN4 is involved in Fe-S cluster biogenesis, as knockout cells decrease Fe-S-containing
proteins, regulate IRP1 and IRP2 expression and decreased ETC activity [252] . In another study, SFXN4
was localized to the inner mitochondrial membrane [253] . Variants in SFXN4 induce intrauterine growth
retardation, microcephaly, vision impairment, and macrocytic anemia [253] .

Mitochondrial dynamics: membrane transport and fusion/fission dynamics
The cell biology of mitochondrial dynamics is expanding our understanding of intracellular signaling
coupled to cellular mitochondrial networks. Mitochondrial dynamics orchestrate metabolism, regulate
cell pluripotency, cell division, differentiation, senescence, and cell death. The complete description is
beyond the scope of this article, but excellent reviews exist [41,254,255] . Briefly, various physiological functions
are intimately related to mitochondrial morphology as driven by fusion and fission. Fission involves the
splitting a mitochondrion into smaller, more discrete mitochondria. Depending on the cellular context,
fission can accelerate cell proliferation, generate oxygen radical species, or facilitate mitophagy. Fusion
creates a more interconnected mitochondrial network that enhances communication with the ER. Fusion
also allows diluting the accumulated mtDNA mutations and oxidized proteins. Fission and fusion are
mediated by a number of guanosine triphosphatases (GTPases) and small outer membrane partners:
mitochondrial fission factor (MFF), mitochondrial fission 1 protein (FIS1), mitochondrial elongation
factor, mitofusion-1 (Mfn-1) and -2 (Mfn-2), and inner membrane protein (OPA1). There are also small
vesicles excised from mitochondria, mitochondrial derived vesicles (MDVs), which contain OMM and
IMM proteins that can fuse with other organelles. The exact role of MDVs has not been fully elucidated but
they are thought to be communication vesicles to other organelles. Their formation is not related to GTPase
or dynamin function. Other budding vesicles, referred to as mitochondrial-derived compartments (MDCs),
also carry outer and IMM proteins. These vesicles are dynamin-mediated fission products and are thought
to be involved in quality control. Mitochondria are also involved in apoptosis in association with BCL-2,
which controls the mitochondrial OMM permeabilization and subsequent fragmentation with cytochrome
C release. The OMM has mitochondrial antiviral signaling proteins (MAVS) that are involved in innate
immunity and signal transduction.

There are several functions involved in these dynamic processes. Mitochondrial biogenesis is regulated
by cellular energy demands and compensation for cell damage. This proliferation and pruning process
is mediated by the peroxisome proliferator-activate receptor g coactivator 1a (PCG-1a) with the fusion
mediator Mfn-2. Fission and fusion dynamics are involved in a quality control process named mitophagy.
This autophagy process maintains cellular health by isolating depolarized and hence dysfunctional
mitochondria by fission, while coordinating downregulation of fusion mediators preventing persistence
of damaged mitochondria by active degradation. Mitochondria are linked to the ER at specialized
regions known as mitochondria-associated ER membranes by protein bridges (MERCs). A key tethering