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INNOSC Theranostics and
Pharmacological Sciences Mitochondria and aging

can be passed on to offspring. Moreover, mtDNA is more DNA in most mammalian cells. 17,18 Mitochondrial genes
prone to stress-induced damage owing to the deficiency are almost exclusively inherited from the maternal
of protective histones, reactive oxygen species (ROS) parent. However, several important exceptions have
generation in the inner membrane, and limited repair been reported. 19-21 The mtDNA is structured into
mechanisms. Thus, it possesses a mutation rate expected distinct protein-DNA complexes known as nucleoids
9,10
to be 10–20 times higher than that of nuDNA. These (mt-nucleoid), and these can be observed under the
mtDNA modifications can have serious effects on ATP microscope as punctate structures located on the matrix
levels and other cellular processes associated with critical surface of the mitochondrial inner membrane. 22-25 The
and debilitating diseases, including neurodegenerative mt-nucleoid is an mtDNA transmission unit that facilitates
disorders (NDs) encompassing Alzheimer’s disease (AD), its accurate transfer into daughter cells during cell division
Huntington’s disease (HD), multiple sclerosis, Parkinson’s and also serves as a platform for mtDNA replication. 26-30
disease (PD), and amyotrophic lateral sclerosis. Each of Furthermore, transcriptional factor A mitochondrial,
these diseases is associated with distinct regions of the mitochondrial single-stranded DNA-binding protein
brain and abnormalities involving specific proteins. (mtSSB), and Twinkle protein have been demonstrated
10
Nevertheless, this organelle has developed multiple stress- to colocalize with mt-nucleoid in intramitochondrial foci
31
response strategies that contribute to the re-establishment in living cells. Mammalian mtDNA is approximately
of cellular homeostasis through mitochondria-associated 16.5 kb in length and comprises 37 genes required for
32
ubiquitination and proteasomal degradation systems, optimal mitochondrial function. It is previously known
which usually prevent mitochondrial proteotoxicity and that mtDNA encodes two rRNAs, twenty-two tRNAs, and
11
remove damaged elements, including protein turnover. It thirteen polypeptides that form the core components of
is noteworthy that mitochondria, as a complex organelle, ETC Complexes I, III, IV, and V, which are required for
is controlled by both nuclear DNA (nuDNA) and its own the oxidative phosphorylation process (OXPHOS). 33,34
DNA (mtDNA) and that cellular homeostasis depends The nuDNA encodes the majority of mitochondrial
on the dynamic interaction between the nucleus and proteins (about 1500), which are produced in the cytosol
the mitochondria. Furthermore, mitochondria have and transported into the mitochondria. 35,36 Furthermore,
retained some of the original bacterial genomes that mtDNA has no introns, no gaps between genes, and no 5’
coevolved with the nuclear genetic material. However, or 3’ non-coding regions. 37,38 The mtDNA consists of two
they import over a thousand proteins that are essential strands: the heavy (purine-rich) strand, which encodes
for diverse mitochondrial functions encoded in the most of the information, and the light (pyrimidine rich)
nucleus. Furthermore, the coordination of nuclear and strand, which encodes the genetic information for only
39
mitochondrial genomes in a cell regulates metabolism, one polypeptide and eight tRNAs. Among the 14 known
epigenetic alterations, and a variety of activities critical DNA polymerases in humans, DNA polymerase gamma
for the survival and activity of mammalian cells, reflecting (Pol γ) is responsible for the replication and repair of
their close relationship. 12-14 According to several studies, mtDNA and is encoded by the POLG gene. 40-42
mitochondrial functions decline significantly throughout
aging, followed by a reduction in cell activity, which is 3. Damage and mutations to mtDNA
4,15
associated with the development of a wide range of age- contribute to aging
related diseases. Mitochondrial dysfunction is a broad Although both nuDNA and mtDNA are constantly
term that encompasses various biological processes, exposed to external agents such as ionizing radiation,
including alterations in mitochondrial protein synthesis, radiation, environmental toxins, and many therapeutic
mitochondrial morphology and content, mitochondrial drugs, mtDNA is more susceptible to toxic chemicals
metabolism, and degradation pathways, and changes than nuDNA due to its proximity to OXPHOS sites,
in the functionality of electron transport chain (ETC) lack of histone protection, and low repair activity when
complexes. The present review outlines the role of damaged. 43-47 ROS-induced mtDNA damage is thought
16
mitochondria in the aging process that occurs through to be the principal cause of mutagenesis in mitochondria,
multiple distinct pathways. Moreover, we propose new resulting in both mtDNA mutations and deletions.
48
areas that could facilitate mitochondrial-targeted therapies Furthermore, mtDNA is required for the maintenance
for the treatment of age-associated diseases. and regulation of mitochondrial functions, and its
2. mtDNA structure and features mutation rate is believed to be 10 to 20 times higher
than that of nuDNA. Furthermore, lipophilic cations
9
Mitochondria possess circular, supercoiled, and double- tend to accumulate in mitochondria, particularly in the
stranded DNA, which accounts for 0.1 – 2% of total mitochondrial membranes, due to the negative charge on

Volume 7 Issue 2 (2024) 2 doi: 10.36922/itps.1726