Page 31 - ITPS-7-2

INNOSC Theranostics and
Pharmacological Sciences Mitochondria and aging

subset of mitochondria is supported by the engagement of mechanism, the mitochondrial-derived vesicle (MDVs)
the mitochondrial kinase PINK1 (PTEN-induced putative pathway, was shown to function during the early stages of
kinase protein 1). When mitochondria lose membrane cellular stress and has a key role in mitochondrial oxidative
potential, PINK1 accumulates on the mitochondrial stress to maintain stable mitochondrial function. 242
surface, resulting in the recruitment of the cytosolic
protein Parkin, which regulates the mitochondrial 8. Dysfunctional mitochondria and
protein ubiquitination and subsequently, engulfment of inflammation during aging
damaged mitochondria by membranes that then fuse with As discussed, MQC maintains healthy mitochondria
lysosomes, a process known as mitophagy. Mitophagy via the repair or selective elimination of damaged
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was discovered to be a crucial process for preserving mitochondria in cells via a series of adaptive responses
cellular health and homeostasis. Surprisingly, the BCL2 encompassing mitochondrial fusion and fission,
protein family was shown to take part in both mitophagy mitophagy, and mitochondria-dependent cell death.
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processes and mitochondrial dynamics, placing them MQC dysfunction during aging causes an accumulation
in the spotlight of mitochondrial regulatory elements. of damaged mitochondria, which contributes to aging
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Studies reported that dysregulation of mitophagy and and a variety of age-related diseases. Studies reveal that
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damage to mitochondria have been observed in several when MQC is defective, mitochondrial-derived damage-
NDs correlated with aging, including PD, AD, and HD. associated molecular patterns (mtDAMPs) such as mtDNA
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Aging escalates the likelihood of the initiation of several and oxidized mtDNA accumulate in the cytosol, which
chronic diseases, usually correlated with the build-ups can activate both intracellular and extracellular immune
in mtDNA mutations, impaired mitochondrial function, pathways affecting age-related disease progression 245,246
mitochondrial mass variation, enhanced cell death, and (Figure 1 [iA–iE]). According to studies, even in the
persistent immune activation that are expected to absence of bacterial infection, mtDAMPs generated as
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happen due to compromised MQC machinery, resulting a result of trauma might cause systemic inflammatory
in the accretion of malfunctioned mitochondria, which response syndrome. Due to the lack of histone proteins,
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consequently elevates immune activation (through ROS mtDNA is vulnerable to degradation and oxidation.
activation) as well as mitochondrial apoptosis (through Furthermore, mtDNA contains hypomethylated CpG
the expression of apoptogenic factors). Several lines of patterns that are identical to those found in bacterial DNA
the study indicate that impaired mitophagy promotes and can be recognized as a pathogen-associated molecular
aging, while improved mitophagy, which is endorsed pattern and hence can induce an inflammatory response.
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by reduced calorie intake and training, advocates a Furthermore, these regions can interact with and activate
health-giving lifetime. For instance, the promotion of membrane or cytoplasmic pattern recognition receptors
mitophagy has been shown to be connected to an increase (PRRs), such as the nucleotide-binding oligomerization
in C. elegans longevity. Lineage-specific expression of domain-like receptor (NLR), the toll-like receptor (TLR),
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PGC-1 (master regulator of mitochondrial biogenesis) in and even the cytosolic cyclic GMP-AMP synthase (cGAS),
Drosophila melanogaster results in a prolonged lifetime which is a stimulator of interferon genes (STING). For
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in this model. Physical activity has been reported to example, Oka et al. revealed that pressure-overload mtDNA
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trigger AMP-activated protein kinase (AMPK) activation, release that escapes autophagic degradation causes TLR9-
which in turn results in phosphorylation of the Unc-51- mediated inflammatory responses in cardiomyocytes and
like autophagy activating kinase 1 (ULK1) and elevated can cause myocarditis and dilated cardiomyopathy. 250
mitophagy in skeletal muscle, which consequently
stimulates mitochondrial biogenesis and enhances health In addition, the cytosolic release of oxidized mtDNA
conditions in murine models. Besides, it has been was shown to stimulate the NACHT-, LRR-, and pyrin
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notably reported that impaired mitophagy significantly domain-containing protein 3 (NLRP3) inflammasome,
affects PD development. Mutations in Parkin and PINK1 a large multi-protein complex that controls caspase-1
proteins participating in the induction of mitochondrial activation, which results in IL-1β and IL-18 secretion and
mitophagy were reported in PD. 237,238 Mitophagy was also an apoptotic activation cascade. In contrast, deletion of
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reported to be linked with AD progression. 239,240 Studies the Nlrp3 inflammasome has been found to reduce age-
have recently demonstrated that tau pathology, a hallmark related activation of the innate immune system, protecting
of AD, disrupts mitophagy by preventing the translocation animals from a variety of age-related diseases. As a
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of Parkin protein to mitochondria. These data underline result, mitophagy plays an important role in inflammation
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the importance of mitophagy for proper mitochondrial prevention by boosting mtDNA clearance from damaged
function and dynamism, which in turn affect personal mitochondria. According to research, circulating mtDNA
health conditions. In addition, a newly identified MQC rises with age and is linked to higher levels of serum

Volume 7 Issue 2 (2024) 9 doi: 10.36922/itps.1726