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INNOSC Theranostics and
Pharmacological Sciences Mitochondria and aging

Figure 1. Mitochondria as a master regulator of aging and therapeutic approaches for aging treatment: (i) The illustration of mitochondria contribution to
the aging process through distinct, but interconnected pathways—(A) oxidative stress due to ROS accumulation can cause dysregulation in mitochondrial
metabolism including impairment of ETC enzyme complexes and impairment in OXPHOS which consequently promotes ROS production associated
with aging and correlated with the development of age-related diseases; (B) consequently, ROS at high levels not only causes oxidative stress and damage
to biological macromolecules (lipids, proteins, and nucleic acids) but also could directly damage the mtDNA, negatively affecting the nuDNA, and genome
integrity which contributes to the aging phenotype; (C) mutations and accumulation of mtDNA can lead to ROS generation and elicit a coordinated
mt
alteration in the nuclear gene expression associated with aging; (D) mitochondria possess internal defense mechanisms, such as UPR , which maintains
mitochondrial proteostasis and biogenesis. However, excessive ROS generation and mtDNA damage result in the impairment or inhibition of these
systems associated with aging; (E) oxidized mtDNA and its release into the cytosol can activate different PRRs and innate immune responses, including
the recruitment of the cGAS-STING pathway and NLRP3 inflammasome, which can drive age-related pathologies such as neurodegenerative disorders;
(ii.) therapeutic approaches for targeting aging and age-related diseases, which are discussed in the manuscript.
Abbreviations: cGAS-STING: Cyclic GMP-AMP synthase-stimulator of the interferon gene; ETC: Electron transport chain;
Mito-CRISPR/Cas9: Mitochondria-targeted clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9; Mito-LND:
Mitochondria-targeted lonidamine; MitoNANOs: Mitochondria-targeted nanoparticles; MitoQ: mitochondria-targeted ubiquinone; mitoTALENs:
Mitochondria-targeted transcription activator-like effector nucleases; mitoZFNs: Mitochondria-targeted zinc-finger nucleases; mtDNA: Mitochondrial
+
DNA; NAD : nicotinamide adenine dinucleotide; NLRP3: NACHT-, LRR-, and pyrin domain-containing protein 3; nuDNA: Nuclear DNA; OXPHOS:
+
Oxidative phosphorylation process; ROS: Reactive oxygen species; TPP : Triphenylphosphonium cation; UPR : Unfolded protein response.
mt
more complex and involves more factors (environmental, of the protein-folding environments in each compartment,
nutritional, metabolic changes, the timing of their occurrence, including the cytosol, endoplasmic reticulum (ER), and
tissue specificity, etc.), which need further vigorous studies. mitochondria. Since all these three compartments are
Moreover, further technological advancements are required exposed to unfolded polypeptides, each has developed a
to quantify the mtDNA mutation load in numerous single dedicated repertoire of specific chaperones to promote
cells at different time points. efficient folding within each cellular compartment. As a
result, any unfolded/misfolded protein stress is identified
4. Mitochondrial unfolded protein response at each cellular compartment and conveyed to the nucleus
(UPR ) in aging for stimulation of the compartment-specific chaperone
mt
The aggregation, misfolding, and tissue accumulation of gene expression. 95,96 In addition, the complex organelle
proteins seriously threaten cellular homeostasis and are architecture of mitochondria, containing two membrane
associated with various human diseases. In addition, barriers, the harmful effects of ROS, and the susceptibility
94
various mechanisms have evolved individually in the highly of mtDNA to acquiring mutations make the mitochondrial
compartmentalized eukaryotic cell to guarantee the integrity environment susceptible to the accumulation of unfolded

Volume 7 Issue 2 (2024) 4 doi: 10.36922/itps.1726