Page 27 - ITPS-7-2

INNOSC Theranostics and
Pharmacological Sciences Mitochondria and aging

or unassembled proteins. Nevertheless, when misfolded protease. Conversely, when the mitochondria are stressed,
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or unfolded proteins build up beyond the capacity of the mitochondrial matrix protease ClpP cleaves misfolded or
organelle’s chaperones, cells initiate a UPR (Figure 1[iD]). unfolded polypeptides, which are subsequently exported
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The UPR is a mitochondrial-to-nuclear signal transduction to the cytoplasm by HAF-1. Consequently, the increased
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pathway that culminates in the activation of mitochondrial accumulation of peptides in the cytosol leads to a reduced
protection genes such as chaperones and proteases to restore capacity for mitochondrial protein import. 106,113 As a result,
protein homeostasis within the mitochondrial protein- ATFS-1’s mitochondrial import is inhibited, resulting in its
folding environment. Molecular chaperones are found in buildup in the cytoplasm, thus letting ATFS-1 travel to the
both the mitochondrial matrix and the intermembranous nucleus, where, in cooperation with ubiquitin-like protein 5
space (IMS). 97,98 For instance, HSP60 chaperonin, which is (UBL-5) and defective proventriculus 1 (DVE-1) upregulates
localized in the mitochondrial matrix, aids in the folding the expression of mitochondrial chaperones, proteases, and
of tiny, monomeric proteins. Moreover, it comprises Hsp60 different metabolic and detoxification enzymes. 114,115 In such
and Hsp10 subunits, which together form a barrel-shaped a setting, cross-compartment synchronization seems to
complex. 99,100 In addition to HSP60 chaperonin, there is be an essential factor in maintaining protein homeostasis
mitochondrial HSP70 (mtHSP70), which is located in the during UPR . The activation of UPR is thought to be one of
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matrix and is known to perform various functions. The the mitochondrial processes that protect against numerous
mtHSP70 forms the core subunit of the machinery, called types of aging-causing damage, with complex effects on
“import motors,” which provides a driving force for the longevity. Notably, studies show that the activation of
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proteins imported into mitochondria. 98,101 Other studies UPR mechanisms by downregulation of ETC complexes I
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show that mtHSP70 assists in the folding of imported and IV promotes longevity. 117-119 Moreover, UPR activation
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polypeptides in the matrix while preventing their has been connected to the extension of lifespan caused by
aggregation in the matrix. 102-104 In addition, mitochondria various types of bacteria, possibly through enhanced
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have a number of proteases that are positioned in the inner production of the polysaccharide colanic acid (CA), which
membrane and matrix, which mediate the destruction of regulates mitochondrial dynamics and UPR in the host
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misfolded or incorrectly assembled proteins. Inside the C. elegans. Another study showed that ATFS-1 enhances
mitochondrial matrix, the protein-folding environment is longevity in long-lived nuo-6 mitochondrial mutants
monitored and protected. When accumulating unfolded by activating a variety of stress response pathways.
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proteins are detected, a mitochondria-to-nucleus signal Furthermore, the longevity of two long-lived mitochondrial
transduction pathway sends a signal from the mitochondria mutants, namely clk-1 and isp-1, was likewise demonstrated
to the nucleus via the cytosol. This frequently results in to be decreased by the knockdown of ubl-5 and dve-1 which
subsequent overexpression of the relevant chaperone- are the regulators of UPR . In addition, studies suggest
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encoding genes and quality control proteases, guaranteeing that histone H3 methylation is an essential epigenetic
protein-folding homeostasis at both the protein folding regulator of UPR throughout the lifespan. 122,123 Intriguingly,
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and removal levels. 95 Merkwirth et al. showed that histone demethylases,
Besides, studies show that there are other factors that namely the Jumonji C domain-containing protein family
could activate UPR , including deletion of mtDNA, (jmjd-1.2 and jmjd-3.1) are required for activation of the
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the increase of ROS levels (Figure 1[iD]), alteration of UPR -mediated longevity across species. These findings
mitochondrial dynamics, mitochondrial chaperone or indicate that the epigenetic mechanism modulates the rate
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protease inhibition, and impairment of the ETC. 105-108 of aging downstream of mitochondrial perturbations.
The transcription factor associated with Stress-1’ Moreover, they demonstrated that the gain of function of
(ATFS-1) is a major regulator of UPR in C. elegans demethylases is sufficient to increase lifespan in a UPR -
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and its homolog ATF5 in mammals. Studies show that dependent manner, whereas their loss of function greatly
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this transcription factor is required for the regulation of reduces longevity and UPR . In addition, increasing lines
almost half of mitochondrial stress-responsive genes, such of evidence support the key role of epigenetic regulators
as mitochondrial chaperones and peptidases, as well as namely the sirtuin deacetylase family in the mitochondrial
immune response genes. 106,110 ATFS-1 is known to contain stress response pathways; particularly, SIRT1, SIRT3,
a nuclear localization sequence and a mitochondrion and SIRT7 which contribute to the UPR via different
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targeting sequence (MTS), which allows it to translocate axes. 117,125-129 These findings collectively suggest that UPR
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between the nucleus and mitochondria, mediating plays a key role in specific longevity pathways. However,
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mitochondria-to-nuclear communication. 111,112 In the relationship between UPR and longevity seems more
addition, under non-stress circumstances, this protein is complex and requires further studies to ascertain this
imported into the mitochondria and degraded by the Lon relationship.
Volume 7 Issue 2 (2024) 5 doi: 10.36922/itps.1726