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INNOSC Theranostics and
Pharmacological Sciences Mitochondria and aging

a few evident disadvantages have been reported for this undetermined. Nevertheless, mitochondria contribute to
approach, including demanding a CNNNG cleavage site the aging process through multiple distinct pathways that
for I-TevI nuclease. Lately, a substantially unique method are responsive to environmental variations. However, the
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has been described for mtDNA editing, termed double- functional crosstalk between these pathways and their
stranded DNA deaminase (DddA)-derived cytosine effects on the aging process remains largely uninvestigated.
base editors (DdCBEs). 303-306 The DdCBE is comprised of Moreover, the importance of nuclear and mitochondrial
mitoTALE proteins, the interbacterial toxin DddA, and genes and their intricate cross-talk in regulating aging-
also a uracil glycosylase inhibitor (UGI), which is designed related mitochondrial dysfunction adds more complexity
to specifically generate C•G-to-T•A alterations in human to our understanding of the aging process. mtDNA is
mtDNA with extreme target accuracy. Surprisingly, susceptible to accumulating mutations during the lifetime
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studies have confirmed the successful application of of the cell, resulting in increased heteroplasmy. Beyond
DdCBEs for mtDNA base editing in various species that a certain threshold, heteroplasmy of mtDNA mutations
can be mentioned as human embryos, mice, rats, zebrafish, leads to the disruption of cellular homeostatic mechanisms,
and plants. 304,306-312 Regardless of the bright outcomes of which can be translated into deleterious physiological
applying mitoZFNs and mitoTALENs to mtDNA editing, consequences driving age-associated diseases. 320,321
these approaches have restrictions and boundaries. Either Increased ROS production has been associated
mitoZFN or mitoTALEN techniques should be meticulously
aimed at and devised to identify a certain range of mtDNA with aging. Moreover, mitochondria are considered
sequences, which require a vast amount of effort and a costly both producers and targets of ROS, which participate
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assembly procedure. Furthermore, the present viral- in cell homeostasis by acting as signaling molecules.
based delivery technology (adeno-associated virus, AAV) is However, ROS overproduction has harmful effects on
insufficient for the size of the coding nuclease sequences. cell homeostasis, resulting in age-related oxidative stress
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The newly emerged programmable clustered regularly that can disrupt cell function, mtDNA mutations, the
interspaced short palindromic repeats (CRISPR)/CRISPR- development of various pathologies, or even premature
associated protein 9 (Cas9) genome engineering approach death. Regardless of the unanswered questions about the
has facilitated the above issues as it benefits from a single role of ROS in oxidative stress or as signaling molecules
guide RNA (sgRNA) to distinguish and target a specific and their relationship with mitochondrial dysfunction in
20 bp DNA sequence and a Cas9 nuclease to cleave this aging, antioxidant therapy, such as the administration of
particular DNA sequence. 314-316 Notably, the Mito-CRISPR/ Vitamin E and CoQ10 compounds, seems quite promising
Cas9 system has been published to easily cleave-targeted for slowing down the aging process. However, further
mtDNA in HEK293T cells and zebrafish. Despite the validation is required before their application in clinical
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above, the crucial hurdle to this approach is introducing the trials against age-related diseases.
exogenous sgRNA into mitochondria. While various studies Furthermore, a growing number of studies have linked
have revealed substantial efforts to overcome this challenge, UPR mt activation, mediated by epigenetic modifying
there are still unsolved drawbacks that demonstrate the enzymes, to the aging process and age-related disorders.
ineffectiveness of this approach so far. 301,317,319 A visual However, it is important to highlight that the UPR
mt
summary of the mitochondrial contribution to the aging pathway has yet to be thoroughly described. Besides,
phenotype, alongside its therapeutic approaches targeting mitochondrial perturbation can lead to complex cellular
age-related disorders, is depicted in Figure 1. responses that can take various forms determined by
the type of stressor and target tissue, going beyond the
11. Conclusion currently conceived model of UPR . Hence, progress
mt
mt
Taken together, aging is a time-dependent deterioration in toward the complete characterization of UPR is of
cell performance that is associated with the loss of cellular great importance. As discussed, mitophagy is a highly
homeostasis. Mitochondria are central to various pathways evolutionarily conserved cellular process that specifically
in homeostasis because of their essential contribution degrades damaged mitochondria in response to damage or
to generating ROS, bioenergetics, apoptosis, catabolic stress to maintain a healthy mitochondrial population and,
and anabolic metabolism, and signal transduction. therefore, contributes to MQC. Nonetheless, mitophagy
Accumulating evidence suggests that progressive declines during aging and is linked to age-associated
mitochondrial impairment is associated with numerous diseases, including cardiac dysfunction and neurological
aspects of aging, such as mtDNA mutation buildup, disorders. Thus, interventions that modulate mitophagy
increased oxidative damage, and impaired respiratory emerge as a promising therapeutic approach to counteract
capacity. However, the exact biological cause remains age-related disease development or progression. However,

Volume 7 Issue 2 (2024) 12 doi: 10.36922/itps.1726