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INNOSC Theranostics and
Pharmacological Sciences Mitochondria and aging

the matrix side of the inner mitochondrial membrane. initiated by ROS produced in the mitochondria
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Thus, many biologically toxic compounds and lipophilic (Figure 1[iA–iB]). Furthermore, ROS can cause damage to
drugs that have positive charges are imported from the specific macromolecules such as lipids, proteins, and, most
cytosol and concentrated in mitochondria up to 1000-fold, crucially, mtDNA. The free radical theory of aging has
which can be a threat to mitochondrial components. 50,51 been a popular concept in the area of aging for many years.
mtDNA is found in large quantities (hundreds to thousands Later, the free radical theory of aging incorporated other
of copies per cell). However, a subset of them are affected ideas and evolved into the mitochondrial ‘vicious cycle’
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by mutations. Thus, the proportion of mtDNA mutations theory of aging. It proposes that ROS formation and
can profoundly affect the cellular and clinical phenotype. elevation in oxidative stress can induce damage to mtDNA,
hence gradually giving rise to mtDNA mutations during
The ratio of mutant mtDNA copies to total mtDNA
is sometimes referred to as the heteroplasmy level or life. The accumulation of mtDNA mutations, in turn, leads
to increased mitochondrial ROS generation, which further
heteroplasmy frequency. The phenotypic threshold for increases oxidative stress and the rate of mtDNA damage
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pathogenic heteroplasmies is believed to be 60 – 90% of and mutagenesis (Figure 1[iC]). Consequently, this
mitochondrial genomes inside a cell. 54-56 However, the “vicious cycle” of oxidative damage that is exponentially
outcome is still determined by the specific tissue in which expanding causes tissue degradation and aging, which
they appear, the timing of their appearance, and the total then leads to cell death. 72,73 Recently, the former free
mtDNA content of the cell. 18,57,58 The mtDNA mutations radical theory of aging has been contradicted by several
include mtDNA rearrangements such as inversions or studies. 74-82 Furthermore, another study found that the
duplications, deletions, and point mutations. Nevertheless, longevity of anaerobically grown yeast cells is shorter than
it is known that mitochondrial mutations contribute to that of aerobically produced yeast cells, demonstrating that
multiple diseases. For example, the m.3243A > G DNA aging still occurs under anaerobic conditions with little
mutation in the mitochondrial MTTL1 gene, which ROS. These findings have prompted scientists to speculate
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encodes a specific type of mitochondrial transfer RNA that ROS may perform signaling activities that activate
termed tRNA Leu (UUR) , is the most frequent mtDNA point protective and adaptive responses. 83,84 Moreover, the latter
mutation and can cause a variety of symptoms depending ‘vicious cycle’ theory of aging claimed cautiously that not all
on the extent of heteroplasmy. 59,60 This mutation was mutations drive superoxide production, and in particular,
discovered in 1990 and was associated with a neurological mutations that block the synthesis of cytochrome b would
phenotype known as mitochondrial encephalopathy lactic actually abort any superoxide production at complex III
acidosis with stroke-like episodes. Patients with this that normal mitochondria may exhibit. 71,72 Although some
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mutation typically exhibit signs of a multisystem illness, studies endorsed the above statement, 85,86 other studies,
including stroke-like episodes, hyperglycemia, myopathy, however, did not support the idea that mtDNA mutations
intestinal immobility, deafness, headaches, and seizures. In contribute to higher ROS generation and oxidative stress
general, mtDNA mutations increase with age and appear in mitochondria with age, 66,87,88 placing the mitochondrial
to differ among organs. 10,62-64 Despite mounting evidence “vicious cycle” theory of aging in question. Furthermore,
that increased levels of mitochondrial mutations and several studies suggest that age-related mtDNA mutations
their accumulations contribute to aging and age-related are largely produced during mtDNA replication errors
diseases, 53,65-69 other studies have questioned whether rather than unrepaired damage caused by ROS. 89,90
these mutations ever reach a significant level sufficient to Nevertheless, multiple lines of evidence indicate that
contribute to the aging process. According to studies, the mtDNA point mutations and deletions can accumulate
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production of a defective form of mtDNA polymerase γ, with age, which constantly increases the mutation load
POLG, promotes early death in mice, as well as elevated with metabolic consequences as well as gradual loss of
levels of mitochondrial mutations and premature aging. 66-68 cellular functions, which ultimately results in age-related
These studies vividly connect mitochondrial abnormalities phenotypes. 89-93 However, the precise role(s) mtDNA
to aging. However, the types and levels of mitochondrial mutations play in aging and its related diseases is still being
mutations do not appear to replicate what is observed debated. In addition, the detection and exact physiological
during normal aging. Hence, it is uncertain whether the effects of mtDNA mutations, especially as they pertain to
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rise in mitochondrial mutations with age plays a key role aging, have proven challenging.
in the aging process.
Overall, the mitochondrial “vicious cycle” theory of
In 1956, Harman proposed the free radical theory aging has received both criticism and extensions since its
of aging, which suggests that organisms age as a result introduction, and the relationship (correlative association)
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of the accumulation of oxidative damage over time, between ROS, mtDNA mutations, and aging seems to be

Volume 7 Issue 2 (2024) 3 doi: 10.36922/itps.1726