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Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40 Page 413

Krebs cycle and matrix metabolism
Aconitase 2 (ACO2) encodes the mitochondrial aconitase, which converts citrate into isocitrate via a cis-
aconitate intermediate in the Krebs cycle. Recessive variants produce a variety of phenotypes ranging
from infantile cerebellar-retinal degeneration with optic atrophy, seizures, and severe encephalopathy to
cerebellar ataxia without optic atrophy and spastic paraplegia [336] . Isocitrate dehydrogenase is a tetramer
composed of two a, one b, and one g subunit. This enzyme converts isocitrate to a-ketoglutarate and
generates NADH required at the first step of the ETC reaction. Biallelic recessive variants in the a and b
genes, IDH3A and IDH3B, induce retinal degeneration and encephalopathy [337,338] . Fumarase hydratase
converts fumaric acid to L-malate. Recessive variants induce a broad range of phenotypes ranging from
severe encephalopathy to hypotonia, seizures, cortical malformations, and facial dysmorphism [339] .
Haploinsufficiency predisposes to multiple cutaneous and uterine leiomyomatosis [340] . The MDH2 product,
malate dehydrogenase, converts malate into oxaloacetate. Biallelic recessive variants induce early onset
hypotonia, psychomotor delay, and seizures [341] .

Hereditary spastic paraplegias are heterogeneous neurological disorders with pyramidal symptoms
predominantly affecting the lower limbs. Autosomal dominant spastic paraplegia 9A (SPG9A) and recessive
spastic paraplegia 9B (SPG9B) are induced by variants in the ALDH18A1 gene. The protein product of
1
ALDH18A1 is D -pyrroline-5-carboxylate synthetase (P5CS) that converts glutamate to pyrroline-5-
carboxylate. The intermediate enters proline biosynthesis from glutamate metabolism into ornithine in the
urea cycle [342] .

+
+
Nicotinamide adenine dinucleotide (NAD ) and nicotinamide adenine dinucleotide phosphate (NADP )
+
and their reduced forms NADH and NADPH are cofactors in oxidative-reduction reactions. NAD and
+
NADH are involved in catabolic reactions and NADP and NADPH in anabolic reaction. The ETC is
dependent on NADH for electron transport. The NAD de novo synthesis pathway begins with dietary
L-tryptophan and is converted through a series of reactions to form NAD, the kynurenine pathway.
Recessive variants in KYNU and HAAO encoding two enzymes that convert 3-hydroxykynurenine to
3-hydroxyanthranilic acid to 2-amino-3-carbvoxymuconate-6-semialdehyde have been found to induce
congenital vertebral and heart malformations [343] . There are two NAD kinases, one found in the cytoplasm
and one in the mitochondria [344] . The NAD kinase found exclusively in the mitochondria, NADK2
+
(previously noted as C5orf33), utilizes ATP or inorganic polyphosphate to form NADP . NADK2 also acts
as a molecular chaperone that activates and stabilizes alpha-aminoadipic semialdehyde synthase. Recessive
variants in NADK2 induce malformation of cortical development, ataxia, astatic myoclonic epilepsy, optic
atrophy, and psychomotor retardation [345,346] . This is one of the few mitochondrial diseases that there is a
treatment for: the use of a lysine restricted diet and vitamin therapy with pyridoxal phosphate induces
clinical improvement with resolution of epilepsy and gait improvement [345] .

The double bonds of NADH and NADPH are prone to hydration, which occurs spontaneously at mildly
acidic pH, at elevated temperature, or enzymatically by glyceraldehyde 3-phosphate dehydrogenase to form
R- and S-epimers. When this happens, neither can act as electron donors, but make the metabolite toxic to
cells. The mitochondria have a detoxification enzyme encoded by NAXE, which eliminates the R-epimer [347] .
Rare patients with recessive variants produce a rapidly progressive neurological loss, leading to coma,
global brain atrophy, and death [347] .

There are two fatty acid synthesis pathways in humans, the cytosolic pathway (FAS1) and the mitochondrial
pathway (FAS2). The enzyme trans-2-enoyl-CoA reductase, encoded by MECR, catalyzes the last step in
the FAS2 pathway. Recessive variants in MECR induce childhood onset dystonia and optic atrophy [348] .

The conversion of pyrophosphate to orthophosphate (Pi) occurs by a family of inorganic pyrophosphatases
(PPA), found both in the cytoplasm and within the mitochondrial matrix. The needs of mitochondrial