com
Review
Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Department of Health & Exercise Science, Tianjin University of Sport,
Tianjin 300381, China
b
Department of Military Training Medicines, Logistics University of Chinese Peoples Armed Police Force, Tianjin 300162, China
c
Laboratory of Physiological Hygiene and Exercise Science, School of Kinesiology, University of Minnesota, Minneapolis, MN 55455, USA
Received 12 December 2012; revised 20 January 2013; accepted 22 February 2013
Abstract
Mitochondrial redox metabolism has long been recognized as being central to the effects of aging and the development of age-related
pathologies in the major oxidative organs. Consistent evidence has shown that exercise is able to retard the onset and impede the progression of
aging by modifying mitochondrial oxidanteantioxidant homeostasis. Here we provide a broad overview of the research evidence showing the
relationship between mitochondrial redox metabolism, aging and exercise. We address part aspects of mitochondrial reactive oxygen species
(ROS) metabolism, from superoxide production to ROS detoxification, especially antioxidant enzymes and uncoupling protein. Furthermore, we
describe mitochondrial remodeling response to aging and exercise, which is accompanied by bioenergetics and redox regulation. In addition,
potential mechanisms for redox signaling involved in mitochondrial remodeling and redox metabolism regulation are also reviewed.
Copyright 2013, Shanghai University of Sport. Production and hosting by Elsevier B.V. All rights reserved.
Keywords: Aging; Exercise; Mitochondrial remodeling; PGC-1a; Reactive oxygen species
1. Introduction
The aging process results in a gradual and progressive
structural and functional deterioration of biomolecules that is
associated with many pathological conditions, including
cancer, neurodegenerative diseases, sarcopenia, and liver
dysfunction. In the 1950s, Harman1 first proposed the free
radical theory of aging. This theory contended that free
radicals, produced from normal metabolism, lead to
* Corresponding author.
E-mail address: yzhang@tjus.edu.cn (Y. Zhang)
Peer review under responsibility of Shanghai University of Sport
2095-2546/$ - see front matter Copyright 2013, Shanghai University of Sport. Production and hosting by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jshs.2013.03.006
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H. Bo et al.
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H. Bo et al.
investigated UCP2 and UCP3 expression along with mitochondrial respiratory function and ROS generation in rat heart
and skeletal muscle during and after an acute bout of prolonged exercise up to 2.5 h. The data demonstrate that UCP2/
UCP3 expression can be rapidly upregulated during prolonged
exercise, and a coordinated regulation to reduce ROS generation and to preserve mitochondrial respiratory function.28,29
Noticeably, MnSOD expression and enzyme activity was not
up-regulated until after exercise under this experimental
condition. Thus, our data suggest that during an acute bout of
demanding exercise, the primary strategy of mitochondria to
reduce oxidative stress is decreasing the production of O2 by
overexpressing UCP2/UCP3, instead of enhancing the
removal of O2 by overexpressing MnSOD.
Our study also demonstrated that endurance training
attenuated acute stress-induced UCP2/UCP3 expression and
activity in rat. Meanwhile, endurance training significantly
elevated MnSOD activity and protein level.28,30 Similarly,
Noland et al.31 reported that acute exercise increases skeletal
muscle UCP3 expression in untrained but not trained humans.
These findings raised some interesting questions regarding the
relationship among mitochondrial respiratory uncoupling,
ROS generation, antioxidant defense, and ATP synthesis. An
ameliorated exercise response of UCP2/UCP3 after training
could be viewed as a compensatory mechanism to avoid
excessive sacrifice of oxidative phosphorylation efficiency and
heat production. McLeod et al.32 reported that in mitochondria
from SOD2 knockout mice, ATP production was markedly
reduced due to a higher O2 concentration which activated
UCP2 excessively. Taken together, exercise training adaptation
of MnSOD may enhance mitochondrial tolerance to ROS
production and hence a smaller UCP2/UCP3 activation during
intensive exercise, thus protecting the efficiency of oxidative
phosphorylation.
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old rats. It was shown that an age-associated lack of expression of PGC-1a in response to not only training but also to
cold exposure or triiodothyronine. Recently, Farhoud et al.48
reported that chronic oxidative stress suppresses the gene
expression of PGC-1a through activation of the ubiquitinproteasome system, thereby inhibiting its downstream mitochondrial biogenesis and metabolic gene expression programs.
In addition, chronic inhibition of NF-kB via the pharmacological agent pyrolidine dithiocarbamate (PDTC) was found to
increase PGC-1a level suggesting inactivity might downregulate PGC-1a due to elevated NF-kB activity.49 It could be
presumed that aging related inflammation and subsequent
activation of NF-kB could negatively influence the expression
of PGC-1a and its effect on mitochondrial biogenesis. These
results showed that loss of mitochondrial biogenesis during
aging may be due to a lack of induction of PGC-1a.
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H. Bo et al.
Fig. 1. Western blot analysis of Mfn1 (A), Drp1 (B), COXIV (C), and mitochondrial ATP synthase activity (D) in rat skeletal muscle of 12-week treadmill trained
5-, 15-, and 20-month-old rats and controls. yp < 0.05, yyp < 0.01: trained group compared with control group at various ages; *p < 0.05, **p < 0.01: in control
group, compared with 5 months; #p < 0.05, ##p < 0.01: in trained group, compared with 5 months.
coordinated expression of PGC-1a, which was lineally correlated to Mfn2 and Drp1 levels in human leg muscle. In C2C12
skeletal muscle cells, increasing the production of ROS by
incubation with 300 mM H2O2, results in increased PGC-1a
promoter activity and PGC-1a mRNA expression requiring
the activation of AMPK.63 Ristow et al.64 demonstrated
exercise-induced oxidative stress elevated PGC-1a and
PGC-1b expression and ameliorated insulin resistance, which
were precluded by antioxidants supplementation.
10. Conclusion
A vast body of data has accumulated linking mitochondrial
redox metabolism to the aging process. Therefore, the accumulation of oxidative damage can be decreased either by
lowering the generation of ROS (caloric restriction) or by
regular exposure to a small amount of ROS (such as mild
exercise) that could result in slight oxidative damage, which
then leads to up-regulation of antioxidant systems and
amelioration of mitochondrial remodeling. Signal transduction
by coordinated action of PGC-1, NF-kB, and MAPK (p38)
may be potential regulators in these events. These products
include (1) antioxidant enzymes (e.g., MnSOD, GPx, GCS);
(2) molecules controlling metabolic status and thus ROS
production, (e.g., UCPs, enzymes in fatty acid and glucose
metabolism); (3) transcription factors for mitochondrial
biogenesis (e.g., PGC-1a, NRF-1, Tfam), and (4) a wide range
of proteins that could influence mitochondrial dynamic
remodeling, such as mitochondrial fusion/fission and autophagy proteins. Exercise training is a useful and inexpensive
intervention for preventing aging and degenerative disease, in
which mitochondrial redox metabolism plays a key role.
Acknowledgments
This work was supported by research grants from the National
Natural Science Foundation of China (No. 31110103919,
31200894, 31000523, 30771048, 30470837, 31071040, and
30270638), Tianjin Municipal Sci-tech-innovation Base Project
(No. 10SYSYJC28400), Tianjin Science and Technology
Planning Project (No. 12JCQNJC07900), and General Administration of Sport of China Basic Project (No. 10B058).
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