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replication element, the light strand replication origin (OL), is situated externally to this region [2,21] . In
addition, the D-loop segment is triple-stranded and contains a unique 650 nucleotide strand located between
both the heavy and light strands, named 7S DNA, as determined by its sedimentation attributes [2,22] . Within
the D-loop, 7S DNA is bound to the light strand, which displaces the heavy strand . While the entire
[23]
function of 7S DNA is not completely defined, it has been hypothesized that it participates in mtDNA
transcription and replication .
[2]
DNA sequencing analysis has revealed unique regions on both strands of the human mitochondrial genome
coding for 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and 13 polypeptides that function exclusively
for mitochondrial-related processes. The 13 polypeptides corresponding to respiratory chain subunits are:
complex I subunits (7), complex III subunit (1), complex IV subunits (3), and complex V subunits (2) .
[2]
However, not all of the vital mitochondrial proteins are translated inside of the mitochondrion; only about
[24]
1% of mitochondrial proteins are synthesized within the mitochondrial matrix . Mitochondrial proteins
that are nuclear encoded and subsequently translated in the cytosol must be trafficked and integrated into the
mitochondrion. Only precursor proteins containing a specialized signal sequence are granted entry across
the mitochondrial membranes using specialized multimeric protein translocator complexes: translocase of
the outer membrane (TOM), the translocase of the inner membrane (TIM), and the OXA complex.

Divergent from nuclear DNA, mtDNA is not packaged like chromatin; rather it is organized into structures
known as nucleoids. Since mtDNA lacks the attributes embodied in chromatin, the nucleoid structure
functions to provide sequential regulation of mtDNA related processes, while simultaneously protecting
against degradation and damage . Dependent on the cell line, nucleoids contain between one and eight
[2]
mtDNA copies . While it remains challenging to fully characterize the composition of a nucleoid, the
[7]
protein TFAM (transcription factor A of mitochondria) functions as a critical component of packaging
that non-selectively binds to mtDNA to create negative supercoiling, thereby significantly compacting
the mitochondrial genome [2,22] . A unique attribute is their close association to the mitochondrial inner
membrane, via anchoring, as visualized by high resolution microscopy .
[2]
Multiple copies of mtDNA can be contained within a single cell and are either identical (homoplasmy) or
[2]
dissimilar (heteroplasmy) . Some potential reasons mitochondrial genomes may become heteroplasmic are:
maternal transmission, location of the mtDNA relative to oxidative phosphorylation, lack of histones, and
the truncated efficiency of the mitochondrial DNA repair machinery . While some mtDNA mutations may
[2]
be considered pathogenic, there also exists a potential for others to have no effect. A pathogenic mutation
can be overcome if the amount of non-mutated (wild-type) mtDNA is greater than mutated mtDNA within
the same cell. While an advantage lies in this scenario, the opposite circumstance also exists and can induce
deleterious effects. When the amount of mutated mtDNA is greater than non-mutated mtDNA, it will likely
result in a mitochondrial-related disease. This phenomenon is known as the threshold effect and is a critical
component regarding the existence of numerous mitochondrial myopathies . Further, due to these varying
[2]
ratios of normal to diseased mtDNA, its imbalance will likely cause a spectrum of mitochondrial defects
leading to a variation in symptom severity per patient.

MITOCHONDRIAL DISEASES
Overview
Mitochondrial diseases are a collection of illnesses arising from defects relative to the respiratory chain
and oxidative phosphorylation . As of current, the United Mitochondrial Disease Foundation (UMDF)
[25]
has compiled a comprehensive list of varying mitochondrial diseases [Table 2] . Mitochondrial diseases
[26]
can either involve affecting a single organ or numerous organ systems, which often phenotypically have
a neurologic and myopathic presentation . These diseases have an ability to arise from either nuclear or
[27]