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Page 390 Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40

The process of OXPHOS is not completely efficient, and some unpaired electrons escape to form reactive
oxygen species. The reactive oxygen species feed back to the nuclear compartment in the cell to help
regulate nuclear control of mitochondrial function. Proton motive force is also intimately involved in
calcium homeostasis in conjunction with the endoplasmic reticulum (ER), as well as apoptosis, solute and
ion transport, protein import, and biosynthetic reactions within the matrix [Figure 1] [44-46] .

The matrix lies within the IMM. The inner membrane contains a special phospholipid, cardiolipin which
is a four-tailed molecule. The structure of cardiolipin allows the inner membrane to take on a highly
curved structure, inner membrane or cristae. Within the cristae lies the matrix, which contains hundreds
of enzymes responsible for production of ATP and mitochondrial metabolism. The Krebs cycle and beta
oxidation enzymes responsible for formation of NADH and FADH are found in the matrix. The matrix
2
also contains enzymes needed for amino acid biosynthesis, and oxidation of several specific amino
[47]
acids . Each mitochondrion contains 2-10 copies of mtDNA, found within the matrix. In addition,
enzymes involved in the urea cycle, DNA synthesis, metabolism of fatty acids, iron-sulfur biosynthesis, and
functional proteins for apoptosis/autophagy and fusion are located within the matrix [48,49] .

Mitochondrial genetics
The human mtDNA is a 16,569 kilobases (kb) closed-circular double-stranded molecule that encodes
[5]
13 polypeptides, 22 transfer RNAs (mt-tRNAs), and 2 ribosomal RNAs (mt-rRNAs) . All nucleated
cells contain between 100 and 10000 copies of mtDNA; higher numbers of mtDNA and mitochondria
are regulated by energy demands. With extremely rare exceptions, all mtDNA is maternally-inherited.
mtDNA is packaged in protein-DNA complexes, nucleoids, which also contain the machinery required for
mtDNA replication, transcription, repair, packaging, and stability [50,51] . The unique nature of mitochondrial
inheritance and multiple mitochondrion per cell with each mitochondrion having many mtDNA molecules,
has produced several unique physiological features. Homoplasmy is a term describing when all mtDNA
molecules contain a relevant gene in question has the identical sequence. Heteroplasmy is the term where
two or more variant populations of a particular mtDNA sequence exist within one cell. The heteroplasmic
level/load of a variant can vary between tissues in a single individual, complicating disease detection . Not
[52]
all mtDNA variation leads to disease: some variants are neutral, others may confer a selective advantage
to the cell or organism, and still others are risk factors for disease . When disease causing, pathogenicity
[53]
[54]
is determined by the nature of the mutation and relative abundance or heteroplasmy level . The relative
amount of variant heteroplasmy that produces disease is named threshold, and it can vary from tissue to
tissue. This variation of levels between tissues types can produce a mosaic of organ dysfunction within an
[52]
individual . Most pathological variants are considered “recessive” because high levels of heteroplasmy
(threshold) are required to manifest cellular defect or clinical phenotype. However, heteroplasmy cannot
always explain the phenotype variability seen. For example, in LHON patients, being male is a predictor for
disease expression, even though both females and males in the same family express 100% homoplasmy of
the mtDNA pathological variant .
[7]
Electron transport chain disorders
The 13 mtDNA encoded proteins are essential proteins encoding subunits of the ETC, Complexes I, III,
IV, and V. The subunits encoded by mtDNA are all essential hydrophobic components of ETC (OXPHOS)
housed within the inner membrane. There are another 79 subunits encoded by nuclear DNA, including all
subunits of Complex II . Pathological variants have been reported in all 13 mtDNA structural genes, as
[55]
well as mt-tRNA and mt-rRNA genes [56,57] .

Complex I (NADH: ubiquinone oxidoreductase) is the largest component of the ETC system, comprising
45 subunits. Electrons, in the form of NADH, enter ETC at Complex I. Complex I is involved as part of
the supercomplex consisting of one Complex I, two Complex III, and one Complex IV unit aggregates,