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INNOSC Theranostics and
Pharmacological Sciences Mitochondria and aging

5. Mitochondrial oxidative stress in aging oxidative modulation of substantial macromolecules
(lipids, proteins, carbohydrates, and DNA) 2,144 and can be
Mitochondria are known to generate various types considered as oxidative stress markers. 2,148 When there is an
of “reactive species” as side products of oxidative imbalance between the formation and clearance of RONS,
phosphorylation, including the reactive oxygen/nitrogen oxidative stress occurs. In this regard, antioxidants
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species (RONS). The increase in RONS production is safeguard biological entities from deleterious free radicals
linked to oxidative stress, which can cause oxidative comprising endogenous as well as exogenous molecules.
damage to cells via apoptosis, autophagy, and inflammation Endogenous antioxidants consist of enzymatic and non-
if not eliminated efficiently by the cellular antioxidant enzymatic forms.
defense system. 130,131 Moderate or low amounts of RONS,
on the other hand, can operate as signaling molecules The major enzymatic antioxidants are catalase (CAT),
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in the cell. 132-134 Even though mitochondrial RONS take SOD, and glutathione peroxidase (GSH-Px). As discussed
part in numerous physiological processes, including before, SOD transforms O • into H O , which further
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epigenetic modifications and disease progression, such breaks down to oxygen and water by CAT, inhibiting the
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as cancer, 136-141 the mechanisms of mitochondrial RONS production of hydroxyl radicals. Furthermore, GSH-Px
have not been fully understood. Moreover, age-associated transforms hydroxyl radicals and peroxides into non-toxic
functional disorders can arise from RONS, which are compounds through the oxidation of reduced glutathione
by-products of oxygen and nitrogen originating from (GSH) into glutathione disulfide (GSSG), and then
various sources, and their negative effects are compensated glutathione disulfide is reduced to the sulfhydryl form
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by antioxidant mechanisms. 2,142 Hence, RONS play a glutathione (GSH) by glutathione reductase. Further
significant role in the development of age-associated antioxidant enzymes to be mentioned are glutathione-S-
diseases. 2,143 RONS can be derived from endogenous as transferase and glucose-6-phosphate dehydrogenase. 2,149
well as exogenous sources. Endogenous sources consist Non-enzymatic antioxidants are compounds that
of myeloperoxidase (MPO), nicotinamide adenine react with RONS and abate the free radical chain
dinucleotide phosphate (NADPH) oxidase, angiotensin reactions: α-tocopherol (vitamin E), β-carotene, and
II, and lipoxygenase. 143,144 O • is another form of RONS bilirubin are present in the blood, whereas uric acid and
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that is produced by the reduction of molecular oxygen albumin comprise 85% of antioxidants in plasma. 2,150
with supplied electrons carried by NADPH during cellular Exogenous antioxidants consist of ascorbic acid
respiration. O • can dismutate into hydrogen peroxide (vitamin C), which breakdown hydroxyl and superoxide
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(H O ) by superoxide dismutase (SOD). 2,145 H O is not radical anion, α-tocopherol (vitamin E), which plays a
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considered a free radical since it does not contain unpaired role in lipid peroxidation of cell membranes, phenolic
electrons. However, it can produce highly reactive hydroxyl antioxidants, selenium, oil lecitinas, zinc, and drugs such
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ions (OH•) through the Fenton or Haber-Weiss reactions. as acetylcysteine. 2,151 These molecules usually function
Hydroxyl radicals are extremely reactive, particularly with as scavengers of free radicals or can even modulate the
phospholipids found in cell membranes and proteins. activity of enzymatic systems. As already mentioned, the
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On the other hand, H O , MPO, and chloride can be contribution of ROS to aging is controversial. Numerous
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transformed into hypochlorous acid, a ROS-specific studies have demonstrated that inhibition of oxidative stress
cellular damaging protein. 2,145 Nitric oxide (NO) originates corresponds to an increase in lifespan. On the other hand,
from L-arginine via NO synthase (NOS), which forms three some studies have questioned the possibility of ROS as a
main isoforms: (i) Epithelial NOS involved in vascular cause of an aged phenotype. Nevertheless, aged rats were
regulation and vasodilation, (ii) neuronal NOS involved shown to hold higher free radical levels. 153,154 On the other
in intracellular signaling, and (iii) inducible NOS, which hand, reduced levels of antioxidants such as glutathione
is released following numerous endotoxin or cytokine peroxidase (GPx), CAT, and SOD have been reported in
signaling. 2,146 Eventually, the interaction of O with NO can aged rats as well as in humans. 155-161 The action of ROS is
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lead to the formation of a rather reactive molecule called counteracted by antioxidant molecules. Studies suggest that
peroxynitrite (ONOO ). fumarate, a metabolite of the mitochondrial TCA cycle,
- 2,144,145
The exogenous sources of RONS include alcohol, and its derivatives, specifically dimethyl fumarate, have
tobacco, water and air pollutants, drugs (e.g., cyclosporine, antioxidant and anti-inflammatory properties, 163-165 which
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tacrolimus, gentamycin, and bleomycin), heavy or can fight against age-related neurological disorders. 164,166-168
transition metals, cooking (e.g., smoked meat, waste oil, However, their exact molecular mechanism of action
and fat), industrial solvents, and radiation, which are turned remains elusive despite their promising beneficial effects
into free radicals after metabolization inside the body. 2,147 against neurological disorders. The administration of
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Both exogenous and endogenous forms of RONS conduct antioxidants such as Vitamin E compounds, including
Volume 7 Issue 2 (2024) 6 doi: 10.36922/itps.1726