Mitochondrial DNA Mutations and Photoaging

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Mitochondria are organelles whose main function is to generate energy
for the cell. This is achieved by a multistep process called oxidative phosphorylation
or electron-transport-chain. Located at the inner mitochondrial
membrane are five multiprotein complexes that generate an electrochemical
proton gradient used in the last step of the process to tum Adenosine
diphosphate (ADP) and organophosphate into Adenosine triphosphate
(ATP). This process is not completely error free and ultimately this leads to
the generation of reactive oxygen species (ROS), making the mitochondrion

the site of the highest ROS turnover in the cell. In close proximity to this
site lies the mitochondria’s own genomic material, the mitochondrial (mt)
DNA. The human mtDNA is a 16,559-bp-long, circular, and doublestranded
molecule of which 4 to 10 copies exist per cell. Mitochondria do
not contain any repair mechanism to remove bulky DNA lesions. Although
they do contain base excision repair mechanisms and repair mechanisms
against oxidative damage, the mutation frequency of mtDNA is approximately
50-fold higher than that of nuclear DNA. Mutations of mtDNA
have been found to playa causative role in degenerative diseases such as
Alzheimer’s disease, chronic progressive external ophthalmoplegia, and
Kearns-Sayre syndrome [II]. In addition to degenerative diseases, mutations
of mtDNA may play a causative role in the normal aging process,
with an accumulation of mtDNA mutations accompanied by a decline of
mitochondrial functions. Recent evidence indicates that mtDNA mutations
are also involved in the process of photoaging [4].
Photoaged skin is characterized by increased mutations of the mitochondrial
genome [1,12,13]. Intraindividual comparison studies have revealed
that the so-called common deletion, a 4,977 base pair deletion of mtDNA,
is increased up to IO-fold in photoaged skin, as compared with sun-protected
skin of the same individuals. The amount of the common deletion in human
skin does not correlate with chronological aging [14], and it has therefore
been proposed that mtDNA mutations such as the common deletion
represent molecular markers for photoaging. In support of this concept it
was shown that repetitive, sublethal exposure to UVA radiation at doses
acquired during a regular summer holiday induces mutations of mtDNA in
cultured primary human dermal fibroblasts in a singlet oxygen-dependent
fashion [15]. Even more importantly, in vivo studies have revealed that
repetitive three-times daily exposure of previously unirradiated buttock skin
for a total of two weeks to physiological doses of UVAradiation leads to an
approximately 40% increase in the levels of the common deletion in the
dermal, but not epidermal, compartment of irradiated skin [16]. Also, use of
sunbeds for a period of only 3 months increased mtDNA mutagenesis in vivo
in human skin [17]. Furthermore, it was shown that, once induced, these
mutations persist for at least 16 months in UV-exposed skin [16]. Interestingly,
in a number of individuals, the levels of the common deletion in
irradiated skin continued to increase with a magnitude up to 32-fold.
It has been postulated for the normal aging process as well as for photoaging
that the induction of ROS generates mtDNA mutations, in turn leading
to a defective respiratory chain and, in a vicious cycle, inducing even more

ROS and subsequently allowing mtDNA mutagenesis independent of the
inducing agent [16]. It is the characteristic of vicious cycles that they
evolve at ever increasing speeds. Thus, the increase of the common deletion
up to levels of 32-fold, independent of UV exposure, may represent
the first in vivo evidence for the presence of such a vicious cycle in general
and in human skin in particular.
The mechanisms by which generation of mtDNA mutations by UVAexposure
translates into the morphologic alterations observed in photoaging
of human skin are currently being unraveled. In general, a cause-effect
relationship between premature aging and mtDNA mutagenesis is strongly
suggested by studies employing homozygous knock-in mice that express a
proofreading-deficient version of PolgA, the nucleus-encoded subunit of
mtDNA polymerase [18]. As expected, these mice develop an mtDNA
mutator phenotype with increased amounts of deleted mtDNA. This
increase in somatic mtDNA mutations was found to be associated with
reduced lifespan and premature onset of aging-related phenoytypes such
as weight loss, reduced subcutaneous fat, alopecia, kyphosis, osteoporosis,
anemia, reduced fertility, and heart enlargement.
In addition, recent studies demonstrate that UVAradiation-induced mtDNA
mutagenesis is of functional relevance in primary human dermal fibroblasts
and apparently has molecular consequences suggestive of a causative
role ofmtDNA mutations in photoaging of human skin as well [19].
Accordingly, induction of the common deletion in human skin fibroblasts
is paralelled by a measurable decrease of oxygen consumption, mitochondrial
membrane potential, and ATP content as well as an increase of
MMP-l, whereas TIMP remains unaltered, an inbalance that is known to
be involved in photoaging of human skin (see below). These observations
suggest a link not only between mutations of mtDNA and cellular energy
metabolism, but also between mtDNA mutagenesis, energy metabolism,
and a fibroblast gene expression profile that would functionally correlate
with increased matrix degradation and thus premature skin aging. In order
to provide further evidence for a role of the energy metabolism in mtDNA
mutagenesis and the development of this “photoaging phenotype,” the
effect of creatine was studied in these cells. This applied the hypothesis
that generation of phosphocreatine, and consequently ATP, is facilitated if
creatine is abundant in cells. This would allow easier binding of existing
energy-rich phosphates to the energy precursor creatine. Indeed, experimental
supplementation of normal human fibroblasts with creatine normalized
mitochondrial mutagenesis as well as the functional parameters of oxygen

consumption and MMP-l, whereas an inhibitor of creatine uptake abrogated
this effect [19].
In another experimental approach, partial depletion of mtDNA from dermal
fibroblasts caused a gene expression profile in these cells reminiscent of
photoaging [20]. Specifically, there was significant upregulation of the
expression of genes involved in collagen degradation, but expression of
genes relevant for collagen de novo synthesis was decreased. Taken together,
these studies strongly indicate that UV-induced mtDNA mutagenesis leads
to photoaging of human skin.

Author : kaabinet

kaabinet

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