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INNOSC Theranostics and
Pharmacological Sciences Mitochondria and aging

mitochondria-targeting ligands to be linked either to amyloid cells (Aβ1-42), which showed decreased Aβ1-42
drug-loaded or free NPs. There are different ligands plaque formation and hyperphosphorylation. Besides,
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that can be linked to NPs depending on the prospective conjugating the polyamidoamine dendrimers with an
strategies and features connected with these ligands, anti-inflammatory and antioxidant agent known as NAC
including prices, synthesis complexity, off-target toxicity, (N-acetyl cysteine) was shown to target the activated
immunogenicity, lengthy blood circulation time, and microglial and macrophage (Mi/Ma) and astrocytes at
delayed clearance from the biological systems. Some of the site of brain injury by penetrating the BBB. Thus, its
these ligands that are conjugated to therapeutic agents to application is a promising tool for treating mitochondrial
improve their efficacy include tetramethylrhodamine- dysfunction associated with neurological disorders.
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+ 270,271
5-isothiocyanate, triphenylphosphonium (TPP ), Overall, the field of mitoNANO has sparked tremendous
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Vitamin E analogs, dequalinium (DQA), cationic interest, and significant efforts are being made to develop
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N-heterocyclic carbenes, and coumarin conjugate. mitochondrial-targeted nanomedicine. Preclinical and
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Among them, TPP is probably one of the most extensively clinical investigations, on the other hand, are required to
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investigated ligands in targeting mitochondria for drug understand the safety of these drug delivery systems as well
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delivery. When TPP is conjugated with NPs loaded with as their potential for a wide range of disorders.
drugs, it increases their lipophilicity and enables them to
escape from lysosomal compartments and easily penetrate 10. Mitochondrial genome editing tool
the mitochondrial membrane bilayers. In addition, cancer against aging
cells facilitate the transfer of the TPP -labeled NPs from Genome editing is a powerful method for eliminating
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the cytoplasm into mitochondria, which can be up to a or replacing genetic abnormalities at specific loci to
hundred times faster than non-functionalized NPs due reprogram or modify their expression. Genome editing
to the mitochondria’s higher negative plasma membrane tools such as zinc-finger nucleases, transcription activator-
potential in cancer cells compared to healthy cells. 264,276,277 like effector nucleases (TALENs), and CRISPR/Cas9 have
For this reason, the mitochondria-targeted agents were already been utilized in a variety of scientific research to
developed by installing a triphenylphosphonium cation generate targeted changes across multiple species. 284-289
(TPP ) joined to diverse bioactive molecules such as Nevertheless, mitochondrial genome editing studies began
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Mito-Met (metformin conjugated with TPP ) and MitoQ with the application of restriction endonuclease enzymes,
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(ubiquinone attached to TPP ), which exhibit enhanced including SmaI, ApaLI, and PstI, designed to be specifically
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lipophilicity and increased cellular uptake. A recent utilized in mitochondria. 290-293 According to a number
study shows the application of mitochondria-targeted of studies, the use of mitochondria-targeted restriction
lonidamine (Mito-LND) by coupling LND to TPP through endonucleases (mtREs) can change the ratio of mutant to
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a connector aliphatic chain could potently inhibit primary wild-type mtDNA heteroplasmy in human somatic cells
lung cancer and suppress brain metastasis from primary and mice models. The reports signified that mtREs notably
lung cancer in an orthotopic animal model, which was reduce the amount of mutated mtDNA. 291,292 Nevertheless,
more effective than LND in both cases. Moreover, Mito- the mtRE strategy has its limitations and challenges. For
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LND could induce autophagic cell death by inhibiting example, a single restriction site (XmaI) has been identified
mitochondrial complexes I and II and stimulating ROS in around 200 mtDNA variants. Further revolutionary
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formation. In addition, curcumin-loaded nanostructured strategies have been established to prevail over the
lipid carriers (NLCs) hold great potential to treat restrictions and boundaries in the application of mtREs.
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neurodegenerative diseases like AD. NLCs are made up The application of mitoZFNs or mitoTALENs, comprising a
of a mix of solid and liquid lipids that can easily cross the MTS, a specific DNA recognition site, and a FokI nuclease,
blood–brain barrier (BBB), one of the most challenging has effectively changed the mitochondrial heteroplasmy
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physiological barriers that exist between the central ratio in earlier studies. 295-300 Zinc finger domains are the
nervous system and peripheral circulation. Curcumin recognition motifs of the mitoZFN that can identify a
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is an herbal extract that has antioxidant as well as anti- 12-bp sequence. In contrast to mitoZFN, mitoTALEN
inflammatory characteristics. When included with NLCs takes advantage of TAL effector proteins as recognition
for targeted administration, curcumin can also reduce motifs that can identify around 17 nucleotides. As well
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the formation of amyloid beta (Aβ) plaque by reducing as the established mitoTALEN strategy, a newer method
the aggregation of amyloid β peptides and decreasing called the mitoTev-TALE approach has been efficiently
neurodegeneration. In addition, silica NPs (SiNPs) were utilized to modulate the mutant mtDNA in cybrid cells.
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also utilized for BBB targeting due to their capacity for In this method, instead of the FokI nuclease, the I-TevI
cellular absorption and accumulation in the intracellular nuclease is attached to TAL effector proteins. Nonetheless,

Volume 7 Issue 2 (2024) 11 doi: 10.36922/itps.1726