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~rnal of
Biomedical
Science
Meeting Report
The Twelfth Joint Annual Conference on Biomedical Sciences, Taipei, April 1%20, 1997
I
J Biomed Sci 1997;4:319-326
Received: June 6, 1997
Accepted: August 15, 1997
Department of Biochemistry and
Center for Cellular and Molecular Biology,
National Yang-Ming University,
Taipei, Taiwan
Role of Mitochondria in
Human Aging
Key Words Abstract
Oxidative damage Mitochondria are the major intracellular source and target sites of reactive
Reactive oxygen species oxygen species (ROS) that are continually generated as by-products of aerobic
Mitochondria metabolism in animal and human cells. It has been demonstrated that mito-
Mitochondrial DNA chondrial respiratory function declines with age in various human tissues and
Mutation that a defective respirators" chain results in enhanced production of ROS and
Aging free radicals in mitochondria. On the other hand, accumulating evidence now
indicates that lipid peroxidation, protein modification and mitochondrial
DNA (mtDNA) mutation are concurrently increased during aging. On the
basis of these observations and the fact that the rate of cellular production of
superoxide anions and hydrogen peroxide increases with age, it has recently
been postulated that oxidative stress is a major contributory factor in the aging
process. A causal relationship between oxidative modification and mutation
ofmtDNA, mitochondrial dysfunction and aging has emerged, although some
details have remained unsolved. In this article, the role of mitochondria in the
human aging process is reviewed on the basis of recent findings gathered from
our and other laboratories.
***~e*samoea*oe,eee,ee
Introduction
Aging is a multifactorial biological process, which is
accompanied by a general decline in biochemical and
physiological functions that leads to the decreased ability
of an individual to respond to a wide range of stresses or
challenges and increased susceptibility to age-associated
diseases and death.
In 1956, Harman [20] first proposed that free radicals
are likely the key factor involved in the aging process. The
main concept was that the accumulation of free-radical-
elicited oxidative damage to macromolecules is a major
contributor to aging. Subsequently, he extended the idea
to suggest that mitochondria are the major target of free-
radical attack that leads to human aging [ 19]. In the past
two decades, the flee-radical theory of aging has been
widely tested and gained great support from molecular
and cellular biological research of aging. Miquel et al. [38,
39] provided great support to this notion by showing that
mitochondrial DNA (mtDNA) damage and lipofuscin
pigment formation in animal tissues are concurrently
increased during aging. In light of the fact that mitochon-
dria are the major intracellular source and vulnerable tar-
get of reactive oxygen species (ROS) and free radicals [10,
43], Linnane et al. [37] further hypothesized that accumu-
lation of somatic mutations in mtDNA is a major contri-
butor to human aging and degenerative diseases. This
modem hypothesis of aging focused on enhanced produc-
tion of ROS and accumulation of mtDNA mutations in
mitochondria of postmitotic cells upon human aging.
KARG E R
Fax +41 61 306 1234
E-Mail karger@karger.ch
www. karger, corn
© 1997 National Science CounciI, ROC
S. Karger AG, Basel
1021-7770/97/0046-0319515.00/0
This article is also accessible online at:
http://BioMedNet,com / karger
Professor Yau-Huei WeiDepartment of Biochemistry, School of Life Science
National Yang-Ming University
Taipei, Taiwan 112 (ROC)
Tel. +886 2 826 71 18, fax +886 2 826 48 43, e-mail joeman@dns.ym.edu.tw
Fig. 1.
Mitochondrial theory of aging and age-related degenera-
tive diseases. The electron transport system in the mitochondrial
inner membrane, which is composed of mtDNA-encoded protein
subunits and nuclear DNA-encoded subunits, is actively involved in
the adenosine-triphosphate-synthesis-coupled respiration that con-
sumes about 95% of the oxygen uptake of the tissue cells. A fraction
of the oxygen is incompletely reduced by 1-electron transfer (mostly
via ubisemiquinone) to generate ROS and organic free radicals,
which may cause oxidative damage and mutation of the nearby
mtDNA molecules that are attached, at least transiently, to the inner
membrane. The oxidatively modified and mutated mtDNA are tran-
scribed and translated to produce defective protein subunits that are
assembled to form defective respiratory enzymes. The impaired elec-
tron transport chain not only works less efficiently in adenosine tri-
phosphate synthesis, but also generates more ROS, which will further
enhance the oxidative damage to various biomolecules in mitochon-
dria. This vicious cycle operates in an age-dependent manner and
results in the widely observed age-related accumulation of oxidative
damage and mutation of mtDNA, which ultimately leads to a pro-
gressive decline in the bioenergetic function of tissue cells in the
aging process. On the other hand, free-radical scavenger systems,
DNA repair systems and mitochondrial turnover for removal of the
oxidative damages by ROS and free radicals become less efficient in
the aging process. Therefore, the accumulation of oxidatively dam-
aged and mutated mtDNA and defective mitochondria and pertur-
bation of mitochondrial turnover act synergistically to cause the gen-
eral decline of biochemical and physiological functions of tissue cells
in the aging process of the human.
In this article, we review recent findings of the oxida-
tive-stress-elicited oxidative damage and mutation of
mtDNA and mitochondrial function decline during hu-
man aging and then discuss the pivotal role of mitochon-
dria in the aging process.
Oxidative Stress and Aging
Mitochondria are the intracellular organelles responsi-
ble for adenosine triphosphate synthesis through the cou-
pling of oxidative phosphorylation to respiration in hu-
man and animal cells [48, 50]. Under normal physiologi-
cal conditions, about 1-5 % of oxygen consumed by mito-
chondria is converted to superoxide anions, hydrogen
peroxide and other ROS [10, 51]. It has been established
that several sites of the respiratory chain are involved in
the generation of ROS [61, 70], and that ROS and free
radicals (e.g. ubisemiquinone and flavosemiquinone) are
continually generated and maintained at a relatively high
steady-state level in mitochondria. It was recently esti-
mated that one normal rat liver mitochondrion can pro-
duce about 3 x
107
superoxide anions in a day [10]. In
fact, within a certain concentration range, ROS assume
important physiological functions such as oxygen burst of
neutrophils and smooth muscle relaxation. In addition,
ROS and free radicals have been demonstrated to act as a
secondary messenger to activate the transcription factors
including NF-~zB and AP-1 [32, 54]. However, an excess
of ROS is harmful to cells [51, 68]. To cope with the ROS,
human cells express antioxidant enzymes including man-
ganese superoxide dismutase (MnSOD), copper/zinc su-
peroxide dismutase (Cu/ZnSOD), glutathione peroxidase
and catalase. MnSOD and Cu/ZnSOD convert superox-
ide anions to hydrogen peroxide, which is then trans-
tbrmed to water by glutathione peroxidase or by catalase.
320 J Biomed Sci 1997;4:319-326 Lee/Wei
Although these enzymes, together with other antioxi-
dants, can dispose of ROS and free radicals, a fraction of
them may escape these cellular defense mechanisms and
cause damage to cellular constituents including DNA,
RNA, proteins and lipids [4, 51 ]. In fact, the concentra-
tion of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), a spe-
cific product of oxidative damage to DNA, has been
shown to increase with age in the tissues of mammals and
insects [2, 17, 52, 57]. Agarwal and Sohat [2] demon-
strated that hyperoxia and X-ray irradiation result in a
substantial increase in the level of 8-OH-dG in the
exposed body site of houseflies. Moreover, it was ob-
served that the specific contents of 8-OH-dG in the flies
overexpressing Cu/ZnSOD and catalase were much lower
than those of the wild-type flies [56]. Furthermore, caloric
restriction was demonstrated to extend the average and
the maximum life spans and to concurrently decrease the
age-related accumulation of 8-OH-dG in various tissues
of the mice [57]. These observations suggest that oxida-
tive damage to DNA plays an important role in aging.
On the other hand, aging-associated accumulation of
inactivated or modified proteins, such as enzymes that
are partially denatured, oxidized and catalytically inac-
tive, has been demonstrated in living organisms including
nematodes, flies and humans [58, 63, 64]. The accumula-
tion of protein carbonyls and the loss of glucose-6-phos-
phate dehydrogenase activity, used as indicators of pro-
tein oxidative damage, have been observed to increase
with age [56, 58, 64]. The intracellular levels of proteolytic
enzymes that hydrolyze oxidatively modified proteins are
insufficient for effective disposal of the aging-associated
increase to aberrant proteins [64]. In the muscle of
Dro-
sophila melanogaster,
the induction of heat shock protein
(hsp) 70 was shown to be responsive to aging [71]. The
same muscle-specific induction of hsp70 was also ob-
served in young flies with mutations in the Cu/ZnSOD or
catalase gene. hsp70 is normally induced in response to
heat and other stresses, and apparently functions to pro-
mote renaturation and folding of proteins, prevent further
protein aggregation and denaturation and facilitate pro-
teolysis of degraded proteins [36, 71]. Several lines of
research have suggested that aging-specific hsp70 expres-
sion may be a result of oxidative damage to proteins [36].
On the other hand, it was shown that the activities of pro-
teases involved in the degradation of aberrant proteins is
markedly decreased in aged animal tissues [33]. It has
long been proposed that pel~urbation of proteolysis is
involved in the formation oflipofuscin and possibly in the
manifestation of animal aging [30, 31]. In fact, lipofuscin
and tipofuscin-like secondary lysosomes are accumulated
in various animal tissues with age [24, 30]. The fluores-
cent pigments are thought to result from cross-linking
between oxidatively modified proteins and lipid peroxi-
dation products, which are concurrently increased during
aging [38, 39]. These observations, together with the
recent findings of wide-spread aging-associated mtDNA
mutations [34, 68, 74], have led us to propose that oxida-
tive damage to cellular constituents and their accumula-
tion with age are the major contributors to the aging pro-
cess (fig. 1).
It has also been observed that the fruit flies with homo-
zygous mutations in either the Cu/ZnSOD or catalase
gene exhibit increased sensitivity to oxidative stress and
have a reduced viability and life span [18, 49]. Because
glutathione peroxidase is absent in
D. melanogaster, Cu/
ZnSOD and catalase thus provide the major enzymatic
antioxidant defenses [59]. Flies that overexpress Cu/
ZnSOD alone or in combination with the overexpression
of catalase were found to exhibit increased resistance to
oxidative stress and have significantly less oxidative dam-
age to proteins and a longer life span [44, 45, 56]. It is
generally accepted that the activities and capacities of
antioxidant systems of tissue cells are declining with age,
leading to the gradual loss of pro-oxidant/antioxidant bal-
ance and accumulation of oxidative damage in the aging
process. These observations provide further support of
the notion that oxidative stress plays an important role in
the aging process.
Oxidative Damage to Mitochondria in Aging
Since mitochondria are the major intracellular source
of ROS, they are thus subjected to direct attacks of ROS
in animal and human cells. It has been recently demon-
strated that the rate of production of superoxide anions
and hydrogen peroxide in mitochondria increases with
age in several mammalian and insect tissues [51, 60-63].
The increase in hydrogen peroxide production ofD.
mela-
nogaster
under aging-elicited oxidative stress was demon-
strated to be related to the oxidative damage to mtDNA
and membrane lipids of mitochondria [60]. Sohal et al.
[63] further demonstrated that the average life span of
dipteran flies is inversely correlated with the rate of mito-
chondrial production of superoxide anions and hydrogen
peroxide and with the level of protein carbonyls in the
tissue cells. Moreover, the age-related increase in the rate
of generation of mitochondriat hydrogen peroxide was
observed to decrease by 40% in the fruit flies overexpress-
ing Cu/ZnSOD and catalase as compared with the wild-
Mitochondrial Role in Aging J Biomed Sci 1997;4:319-326 321
type flies [56]. Therefore, the rate of hydrogen peroxide
release by mitochondria is an important determinant of
the oxidative damage sustained by mitochondria. Ames et
al. [4] first demonstrated that oxidative damage to
mtDNA is much more extensive than that to nuclear
DNA. The specific content of 8-OH-dG of mtDNA was
about 16 times higher than that of nuclear DNA in the
liver of 3-month-old rats. Furthermore, the 8-OH-dG
content in liver mtDNA of the 24-month-old rat was 3
times higher than that of the 3-month-old rat [ 17]. More-
over, the levels of oxidative stress and oxidatively modi-
fied proteins and lipid peroxides in mitochondria have
been shown to increase with age [3, 7, 28, 58]. In addition,
the 8-OH-dG contents in the mtDNA of human dia-
phragm, heart muscle and brain tissues were found to
increase in an age-dependent manner [21, 22]. It has also
been found that mitochondrial glutathione is markedly
oxidized with aging in the rat and mouse [6]. The ratio
between the oxidized and reduced glutathione rises with
age in the liver, kidney and brain of these animals. In the
same study, the 8-OH-dG content of mtDNA was also
found to increase with age in the rat and mouse. Addition-
ally, oral administration ofantioxidants protected against
both glutathione oxidation and mtDNA damage in rats
and mice. These observations suggest a close relationship
between oxidative stress, indicated by glutathione oxida-
tion, and mtDNA damage during the aging process.
Mitochondrial DNA Mutations in Human Aging
Each human and animal cell contains several hundred
to more than a thousand mitochondria, each carrying 2-
10 copies ofmtDNA. Human mtDNA is a 16,569-bp cir-
cular double-stranded DNA molecule [5]. This extrachro-
mosomal genome contains genes coding for 13 polypep-
tides involved in respiration and oxidative phosphoryla-
tion and 2 ribosomal RNA and a set of 22 transfer RNA
(tRNA) that are essential for protein synthesis in mito-
chondria [5, 50]. mtDNA is a naked compact DNA mole-
cule without protective histones and replicates rapidly
without efficient proofreading and DNA repair systems
[12, 14]. It is transiently attached to the mitochondrial
inner membrane, in which a considerable amount of ROS
is continually produced by the respirator-5, chain [27, 28].
These characteristics have rendered mtDNA vulnerable
to attacks by ROS and free radicals generated by the elec-
tron leak of the respiratory chain of mitochondria [46, 67,
681.
In the past 8 years, a number of point mutations, dele-
tions and tandem duplications of mtDNA have been
found in various tissues of aged individuals [13, 15, 29,
34, 35, 42, 69, 72, 74, 77, 78]. These mutant mtDNAs
usually coexist with the wild-type mtDNA within a cell
(heteroplasmy), and the degree ofheteroplasmy often var-
ies in different tissues of the same individual [34, 77, 79].
It has been welt established that many of these mtDNAs-
mutations accumulate with age in postmitotic tissues of
the human [15, 34, 35, 68, 72, 77]. Some of these aging-
associated mtDNA mutations were originally observed in
the affected tissues of patients with mitochondrial dis-
eases. The most common mtDNA mutation is the 4,977-
bp deletion, with a 13-bp direct repeat flanking the 5'- and
3'-end breakpoints at nucleotide position (np) 8,470/
8,482 and np 13,447/13,459, respectively [55, 74]. This
mtDNA deletion was first observed in the muscle of
patients with mitochondrial myopathies, including
chronic progressive external ophthalmoplegia, Kearns-
Sayre syndrome and Pearsons' syndrome [25, 55]. Multi-
ple large-scale deletions of mtDNA have also been found
in various tissues of elderly subjects [67, 68, 72, 77, 79].
Two point mutations at np 3,243 and np 8,344 of
mtDNA, which are, respectively, associated with mito-
chondrial myopathy, encephalopathy, lactic acidosis and
stroke-like episodes (MELAS) syndrome and myoclonic
epilepsy and ragged red fibers (MERRF) syndrome [66]
have been also detected in the muscle of aged individuals
[42, 78]. Additionally, 6 different types of tandem dupli-
cations were found in the D loop region of mtDNA from
the brain, muscle, liver and skin tissues of normal sub-
jects; the incidence and abundance of these tandemly
duplicated mtDNA are increased with age [35, 69].
It is important to note that the proportions of these
mutant mtDNAs in aging human tissues rarely- exeed 1%
[15, 34, 35, 68, 72, 77]. The type and relative proportion
of the aging-associated mutant mtDNA are usually deter-
mined by the choice of primers and PCR conditions.
Recently, a more detailed detection system was designed
for extensive screening ofmtDNA deletions in human tis-
sues [23, 75]. By using 180 kinds of PCR primer pairs, this
system enables one to detect all the possible mtDNA with
deletions over 500 bp. Hayakawa et al. [23] applied this
system to analyze mtDNA from normal hearts of human
subjects of various ages. They observed an extensive frag-
mentation of mtDNA into minicircles with different
sizes. The incidence and abundance of the mutant
mtDNA were found to increase with age and to correlate
well with the oxidative damage to mtDNA [23, 75]. It is
worth mentioning that the aforementioned mutation and
322 J Biomed Sci 1997;4:319-326 Lee/Wei
oxidative damage of mtDNA represent only the tip of the
iceberg of all the mtDNA damages occurring in the aging
process [68].
Although the proportion of the mutant mtDNA was
found to correlate with the 8-OH-dG content of mtDNA
[22, 75], it is poorly understood how oxidative stress or
ROS cause mtDNA mutations. Adachi et al. [1] have
recently demonstrated that ROS may cause large-scale
deletion ofmtDNA in animals. They detected a 4-kb dele-
tion of mtDNA in the heart of Balb/c mice that had
received chronic intraperitoneal injection of doxorubicin,
which is known to induce cardiomyopathy and elicit pro-
found lipid peroxidation of heart mitochondria [ 1]. More-
over, they found that administration of coenzyme Qi0 (a
free-radical scavenger) to the mice could effectively pre-
prevent the mtDNA deletion and decrease the lipid per-
oxide contents of the heart mitochondria. This finding
provides first direct evidence to support the notion that
ROS and free radicals are involved in the large-scale dele-
tion of mtDNA. Although it remains to be established
how mtDNA mutations are initiated or promoted by ROS
and free radicals, recent molecular biological studies have
provided useful information to better understand the
mechanisms of mtDNA mutations.
Sequence analysis of the reported deletions of human
mtDNA revealed that they occurred more frequently
between the origins of replication of the H and L strands
[55, 69] and caused a loss or truncation of genes encoding
tRNA and mRNA that are essential for the proper func-
tioning of mitochondria [68]. The breakpoints of many of
these mtDNA deletions are flanked by direct-repeat se-
quences. Slipped mispairing during DNA replication be-
tween direct repeat sequences [55], homologous replica-
tion [76] and topoisomerase II cleavage [8] have been
suggested to be the possible mechanisms for mtDNA dele-
tions. Presumably due to their stem loop structures, the
mitochondrial tRNA genes are thought to be hot spots for
point mutations [66]. Indeed, more than 10 different
point mutations have been found in the tP, aNA Leu(UUR)
gene [53]. On the other hand, the start sites and the inser-
tion sites of the tandem duplications in the D loop region
of mtDNA have been found to be localized in the regions
containing either a poly C run or a direct repeat sequence
[35, 69]. Moreover, certain regions of mtDNA have been
demonstrated to be particularly sensitive to oxidative
insult of ROS and are prone to mutation [26]. The puta-
tive hot spots for oxidative modification and mutation of
mtDNA could be near or at the unusual structures includ-
ing bent, antibent and non-B DNA sequences in human
mtDNA [26]. These observations suggest that the unusual
structure and/or nucleotide sequence of human mtDNA
are the important factors involved in aging-associated
mtDNA mutations. In addition, it was hypothesized that
genotoxic intermediates of lipid peroxidation may play a
role in eliciting age-associated DNA mutations [28]. The
region of mtDNA that is attached to the ROS-generating
sites in the mitochondrial inner membrane should be
more susceptible to oxidative damage, strand breakage
and mutation [28]. Furthermore, ROS-induced mutagen-
esis has been observed to be DNA polymerase specific
[ 16]. Thus, it is possible that the frequency of occurrence
and the type of mtDNA mutation are determined, at least
in part, by the interaction between mitochondrial DNA
polymerase and the DNA molecules that bear the ROS-
induced oxidative damage during DNA replication.
In addition, several mtDNA mutations have been
reported to occur more frequently in sun-exposed skin at
relatively high levels [47, 72]. This observation suggests
that free radicals generated by environmental insult (e.g.
sunshine, air pollutants and cigarette smoke) may also
play an important role in the induction of mtDNA muta-
tions during the aging process.
Mitochondrial Respiratory Function Declines
with Age
It was first demonstrated in 1989 that the respiratory
function of mitochondria gradually declines with age in
the human liver [73] and skeletal muscle [65], respective-
ly. This phenomenon has been confirmed by several
investigators [48]. The respiratory control, oxidative
phosphorylation efficiency, the rates of resting (state 4)
and adenosine-diphosphate-stimulated (state 3) respira-
tion and the activities of the respiratory enzyme com-
plexes all decline with age in various human tissues [48,
65, 73]. In addition, the number of skeletal and heart mus-
cle fibers deficient in cytochrome c oxidase was found to
increase with age [40, 41]. Since the age-dependent de-
cline of the glutamate-malate-supported respiration was
found to be more dramatic than that of the succinate-sup-
ported respiration, we conjectured that mutation(s) in the
7 genes of NADH dehydrogenase encoded by mtDNA
may be involved in this aging-associated respiratory func-
tion decline. We quickly confirmed this idea by showing
that both the frequency of occurrence and abundance of
the 4,977-bp deleted mtDNA increases with age in the liv-
er [34, 74] and many other tissues [15, 34, 69, 72]. It was
recently observed that the extent of mtDNA mutation
strongly correlates with the progressive decrease in cyto-
Mitochondrial Role in Aging J Biomed Sci 1997;4:319-326 323
chrome c oxidase activity in aging human muscle [48].
Because mtDNA has very little redundancy and high
information density, the large-scale deletions often cause
the removal or truncation of multiple structural genes and
tRNA genes and thereby lead to multiple respiratory-
chain deficiencies. In addition, we recently found several
tandem duplications in the D loop of human mtDNA [35,
69], which contains the replication origin OH and two
transcriptional promoters for each strand of mtDNA [5,
11]. The D loop region is the only and most important
control region in human mtDNA. Therefore, any type of
mutation in the regulatory elements in the D loop of
mtDNA can cause alterations of mtDNA replication and
transcription. In addition, oxidative modification to the
nucleobases could also elicit the errors of mtDNA replica-
tion and gene expression. Therefore, accumulation of oxi-
datively damaged and mutated mtDNA may contribute
to the age-dependent progressive decline of respiratory
function especially in postmitotic cells [4, 39, 48, 67, 68].
On the other hand, it has been reported that the steady-
state levels of mitochondrial transcripts are significantly
reduced during aging of
D. melanogaster;
these changes
correlate very well with the life span of the insect [9]. This
decline in the expression of mitochondrial genes might be
in part caused by damage to mtDNA. Interestingly, it was
recently found that not only cytochrome c oxidase, which
contains subunits encoded by the mitochondrial genome,
but also glutamate dehydrogenase, a nuclear DNA-en-
coded enzyme present in the mitochondrial matrix, grad-
ually lose enzymatic activity during the aging of
D. mela-
nogaster
[9]. These observations suggest that although
mtDNA is more vulnerable to oxidative damage, some
age-related defects in the nuclear genome may also be
involved in aging.
However, it is important to note that the proportions
of the age-related mtDNA mutations in various human
tissues are not so high as those seen in the target tissues of
patients with mitochondrial myopathies [67]. It thus ap-
pears difficult for us to comprehend any significant dele-
terious effect on mitochondrial functions exerted by such
low proportions of the mutant mtDNA in human tissues.
The age-dependent decline of mitochondrial respiratory
function may also be due to the direct ROS damage to
proteins, aside from the deleterious effects of mutation or
oxidative damage to mtDNA. Moreover, it is possible
that all the mutations and oxidative damages to mtDNA
impair, in a synergistic manner, the function of the elec-
tron transport chain and elicit a profound increase in the
rate of ROS generation. A broad spectrum of oxidative
damage and mutation of mtDNA may be effected through
a recently proposed vicious cycle in the aging process [68].
However, it is worth noting that a clear causal relation-
ship between oxidative modification and mutation of
mtDNA, mitochondrial dysfunction and aging remains to
be established.
Concluding Remarks
Mitochondria are responsible for the supply of meta-
bolic energy and are also the main intraceltular source and
target of ROS and free radicals, which are generated as
by-products in the respiratory chain. In the mammalian
cells, the proper assembly and function of mitochondria
are effected through the coordination between gene prod-
ucts encoded by mitochondrial and nuclear genomes [50].
Communication between the nucleus and the mitochon-
drion is essential for delicate regulation of the synthesis of
proteins in the cytosol and their import into mitochon-
dria. ROS and some metabolites that regulate the activa-
tion of specific transcription factors, which may exert
their functions in the nucleus, have been proposed to be
the signals tbr communication between the mitochon-
drion and the nucleus [50, 76]. Besides the effects of the
nuclear genome on the expression of mitochondrial genes,
the mitochondrial genome can also affect the expression
ofnuclar gene-encoded mitochondrial proteins [50]. Oxy-
gen concentration, exercise and hormone levels have been
demonstrated to be able to regulate the mRNA level of
cytochrome c oxidase in the mammal [50, 51]. Therefore,
mitochondria may act as a sensor in regulating energy
metabolism and the release of ROS in response to extra-
cellular stimuli. Moreover, within a certain concentration
range, ROS and free radicals may act as a secondary mes-
senger in some signal transduction pathways [32, 54].
Normally, the overproduced ROS can be scavenged by
enzymatic and nonenzymatic antioxidant systems to pre-
vent deleterious oxidative damage. However, as a result
of an aging-associated increase in ROS generation in the
respiratory chain and a decrease in the intracellular con-
centrations of antioxidants and activities of free-radical-
scavenging enzymes, the age-related elevation of ROS and
oxidative stress is harmful to the cell [51 ]. As the major
intraceltular source ofROS, mitochondria are particularly
vulnerable to oxidative damage. Experimental data from
our and other laboratories have provided ample evidence
to support the notion that mutation and oxidative damage
to mtDNA and mitochondrial respiratory function de-
cline are important contributors to human aging [68].
Although a causal relationship between oxidative modifi-
324 J Biomed Sci 1997;4:319-326 Lee/Wei
cation and mutation of mtDNA, mitochondrial dysfunc-
tion and aging has emerged, the detailed mechanism by
which these molecular and biochemical events cause
aging remains to be established. Understanding of the
age-dependent changes of the structure and function of
mitochondria in the aging process should be of prime
importance in unraveling the molecular basis of aging in
the coming years.
Acknowledgments
Part of the work described in this article was supported by
research grants from the National Science Council (NSC86-2314-
B010-090) and the Department of Health, Executive Yuan, ROC.
Y.-H.W. wishes to express his appreciation of considerable financial
support from the National Science Council in the course of studying
mitochondrial role in human aging.
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