Page 30 - ITPS-7-2

INNOSC Theranostics and
Pharmacological Sciences Mitochondria and aging

metabolic pathways, such as the one-carbon cycle, the Studies have uncovered that stem cell pool maintenance,
tricarboxylic acid (TCA) cycle, and fatty acid oxidation expansion, or depletion are modulated via symmetric and
(FAO), are known to be compartmentalized in the asymmetric division events. 214-217 In addition, stem cells
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mitochondria. Metabolites produced by these pathways can exploit mitochondrial FAO during self-renewal along
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can also serve as retrograde signals. Particularly, many of with glycolysis. Inhibiting FAO in HSCs results in the
these metabolites are produced by the TCA cycle, such as loss of asymmetric division of HSC daughter cells, which
acetyl-coenzyme A, succinyl-CoA, α-ketoglutarate (αKG), is a vital process to maintain the stem cell pool during
succinate, and nicotinamide adenine dinucleotide (NAD ). the simultaneous expansion of stem cell differentiation.
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For instance, it has been demonstrated that the ratio Mechanistically, this process (HSC asymmetric division)
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of αKG to succinate plays a crucial role in maintaining is controlled by the PML-PPARδ-FAO pathway.
pluripotency in mouse mESCs through regulation of Moreover, the same study showed that PPARδ activation
multiple chromatin modifications, including histone H3 using PPARδ agonists increases asymmetric division and
lysin 27 tri-methylation (H3K27me3) and ten-eleven improves HSC functions. In addition, lipid metabolism
translocation (Tet)-dependent DNA demethylation. In is also an important player in NSC proliferation and
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addition, NAD is another important metabolite that links maintenance. 220,221 Specifically, deletion of fatty acid
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the mitochondria to stem cells, and its systemic decline synthase, the key enzyme of de novo lipogenesis, in mouse
has been reported during aging. 202,203 Furthermore, many NSCs was shown to impair adult neurogenesis. Taken
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NAD+-consuming enzymes use NAD as a substrate, together, mitochondria are key organelles that regulate the
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including the cyclic ADP-ribose synthase CD38, SARM1, metabolic status of stem cells; consequently, maintaining
poly-ADP-ribose polymerase (PARP), as well as a family their proper metabolic regulation is critical for lifelong
of seven protein deacylases, namely sirtuins, which health. Moreover, the modulation of pathways associated
are present in the nucleus (SIRT1, SIRT6, and SIRT7), with mitochondrial metabolic dysfunction contributing to
cytosol (SIRT2), and mitochondria (SIRT3 – SIRT5). 204-206 age-related stem cell exhaustion could potentially improve
Alleviated age-dependent NAD availability is associated human health and prevent age-related diseases.
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with decreased activities of sirtuins, eventually disrupting
the crosstalk between mitochondria and the nucleus during 7. Mitophagy and age-associated diseases
aging. 207,208 Reduced NAD levels in NSCs were shown to Being extremely dynamic organelles, mitochondria go
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recapitulate at least some of the phenotypes of stem cells through various processes termed mitochondrial quality
during aging (Figure 1[iA]), while NAD boosting through control (MQC). MQC mainly involves the coordination
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administration of precursor nicotinamide mononucleotide of multiple biological events, including constant fission
(NMN) could repair abnormalities induced by a decrease and fusion, an endless transformation process occurring
in NAD levels in NSCs. Hence, NAD supplementation through biogenesis and mitophagy to affirm mitochondrial
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therapies are considered a therapeutic option to ameliorate homeostasis, morphology, and inheritance. Once
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age-related metabolic diseases. Furthermore, NAD facing challenges through oxidative or bioenergetic stress,
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boosting with the precursor NMN improved impaired mitochondria perform an arranged reaction containing
glucose tolerance by restoring normal NAD levels and morphological and dynamical transformation by triggering
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enhancing either insulin sensitivity or insulin secretion in the specific molecular mechanism that synchronizes
mice with diet- and age-induced diabetes. The observed mitochondrial biogenesis, mitophagy, fusion, and fission.
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effects seem to be partially mediated by the sirtuin (SIRT) Mitochondrial fusion and fission in mammalian cells are
family of NAD -dependent histone deacetylases, which closely supervised by a number of proteins, including
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are known to regulate crucial metabolic pathways. For dynamin 1-like (DNM1L, recognized as Drp1), mitofusin
instance, SIRT3 was shown to regulate global mitochondrial 1 (MFN1), mitofusin 2 (MFN2), and optic atrophy
lysine acetylation levels in an NAD -dependent manner. protein 1 (OPA1). The process of mitochondrial
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Moreover, SIRT3 was shown to be abundant in HSCs, fission was discovered to participate in mitochondrial
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where it regulates stress responses. In addition, the apoptosis and was proposed to be essential for mitophagy,
same study showed that SIRT3 is suppressed during while mitochondrial fusion is linked to an increase in
aging, and its increased levels in aged HSCs improved mitochondrial metabolism. The term “mitophagy,” the
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their regenerative capacity, indicating that the plasticity of selective mitochondrial autophagy, was first named by
mitochondrial homeostasis controls stem cell and tissue John Lemasters. Mitophagy is a procedure during which
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maintenance during the aging process, and hence aging- depolarized, aged, or damaged mitochondria are selectively
associated degeneration can be reversed by a member of removed via double-membrane autophagosome for
the sirtuin family. consequent lysosomal degradation. The detection of this
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Volume 7 Issue 2 (2024) 8 doi: 10.36922/itps.1726