Acetylation of MnSOD directs enzymatic activity responding to
cellular nutrient status or oxidative stress
Ozkan Ozden1, Seong‐Hoon Park1, Hyun‐Seok Kim1, Haiyan Jiang1, Mitchell C. Coleman2,
Douglas R. Spitz2, and David Gius1
1Departments of Cancer Biology, Pediatrics, and Radiation Oncology, Vanderbilt University Medical Center,
Nashville, TN 37232, USA
2Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer
Center, The University of Iowa, Iowa City, IA 52242, USA
Key words: MnSOD, Sirt3, mitochondria, acetylation
Received: 2/24/11; Accepted: 2/27/11; Published: 2/28/11
Corresponding author: David Gius, MD, PhD; Email: David.Gius@vanderbilt.edu
© Ozden et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract: A fundamental observation in biology is that mitochondrial function, as measured by increased reactive oxygen
species (ROS), changes significantly with age, suggesting a potential mechanistic link between the cellular processes governing
longevity and mitochondrial metabolism homeostasis. In addition, it is well established that altered ROS levels are observed
in multiple age‐related illnesses including carcinogenesis, neurodegenerative, fatty liver, insulin resistance, and cardiac
disease, to name just a few. Manganese superoxide dismutase (MnSOD) is the primary mitochondrial ROS scavenging enzyme
that converts superoxide to hydrogen peroxide, which is subsequently converted to water by catalase and other peroxidases.
It has recently been shown that MnSOD enzymatic activity is regulated by the reversible acetylation of specific, evolutionarily
conserved lysine(s) in the protein. These results, suggest for the first time, that the mitochondria contain bidirectional post‐
translational signaling networks, similar to that observed in the cytoplasm and nucleus, and that changes in lysine acetylation
alter MnSOD enzymatic activity. In addition, these new results demonstrate that the mitochondrial anti‐aging or fidelity /
sensing protein, SIRT3, responds to changes in mitochondrial nutrient and/or redox status to alter the enzymatic activity of
specific downstream targets, including MnSOD that adjusts and/or maintains ROS levels as well as metabolic homeostatic
One theme that has emerged in the last several years is
that aging, perhaps better defined as longevity, is a
complex genetic and cellular process that appears to be
regulated, at least in part, by a relatively new gene
family referred to as sirtuins [1,2]. These genes are the
human and murine homologs of the Saccharomyces
cerevisiae Sir2 that has been shown to regulate both
replicative and overall lifespan [3,4]. The sirtuin family
genes have also been shown to direct longevity in C.
elegans and D. melanogaster [1,2] suggesting an
evolutionary conserved need for these proteins in the
cells in multiple different complex species. Sirtuins are
classified as class III histone deacetylases, which
are different than traditional class I and II histone
deacetylases [5,6]. Unlike conventional HDACs,
sirtuins have a variety of substrates ranging from
metabolic enzymes to structural proteins as well as
The mammalian sirtuin family consists of seven NAD+-
dependent protein deacetylases[9-11] that share a
common 275-amino acid catalytic domain and are
localized to the nucleus (SIRT1, 6, and 7), mitochondria
(SIRT3, 4, and 5), and cytoplasm (SIRT2), respectively
. Sirtuins require NAD+ as a cofactor which
mechanistically connects their enzymatic activity to the
metabolism of the cells, and provides link between the
sirtuin activity and energy and stress responses [12,13].
Using these findings as a guide, it seems reasonable to
suggest that sirtuins function as fidelity or watchdog
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proteins signaling proteins that alter the activity of
downstream targets via post-translational modifications
involving protein acetylation to maintain cellular
metabolic homeostasis .
In this regard, lysine acetylation has recently emerged
as an important, and perhaps the primary, post-
mitochondrial proteins [14,15]. Several proteomic
surveys have identified a disproportionately high
number of acetylated proteins in the mitochondria and
many of these proteins are associated with energy
homeostasis [14,16]. Thus, these results suggest that the
mitochondrial acetylome, which is regulated by both
acetyl transferases as well as deacetylase such as
sirtuins, may by the primary means by which the
mitochondrial regulates energy production and ROS
levels to match ATP production with intracellular
energy requirements. In this regard, three of the seven
mammalian sirtuins appear to be localized to the
mitochondria , including SIRT3 that is the primary
mitochondrial deacetylase , suggesting a significant
role for these sirtuins in regulating mitochondrial
metabolism [12,17]. Thus, we and others hypothesized
that SIRT3 may act as a maintenance proteins that
significantly determines the mitochondrial acetylome
that functions by monitoring critical mitochondrial
processes such as the regulation of respiration and/or
metabolite clearance, and initiating a protective and/or
Based on these results, it seems reasonable to propose
that acetylation of mitochondrial proteins may play a
role in maintaining and regulating mitochondrial ROS
levels as well as function. Sirt3 is the main
mitochondrial deacetylase , and genetic knockout of
Sirt3 results in increased ROS, including superoxide
levels, in vitro and in vivo . Thus, we believe it is a
logical extension to hypothesize that SIRT3 is a
regulatory protein, maintaining
homeostasis via changes in the acetylation of metabolic
target proteins, including those comprising the
mitochondrial ROS detoxification system.
We have previously demonstrated that MEFs lacking
Sirt3 exhibit an immortalization permissive phenotype
and the knockout mice spontaneously form well
differentiated, estrogen and progesterone (ER/PR)-
positive mammary tumors . SIRT3 protein levels
are decreased in human breast cancers as well as several
other human malignancies  suggesting that SIRT3 is
a genomically expressed, mitochondrial localized tumor
suppressor. In addition, it has also been shown that the
Sirt3 knockout mice are permissive for other age-related
illnesses including fatty liver , insulin resistance
employed to regulate
, and cardiac hypertrophy [20,21]. These results
identified Sirt3 as a more generalized mitochondrially
fidelity protein and the mice lacking Sirt3 may be useful
in vivo models to investigate human illnesses. One
intriguing finding from all of these manuscripts is that
cells lacking Sirt3 exhibited altered mitochondrial
metabolism as exhibited by increased mitochondrial
ROS and superoxide levels during stress. These results
suggest that the aberrant regulation of the mitochondrial
acetylome, which by definition occurs in murine cells
lacking Sirt3, results in a phenotype permissive for
mouse conditions that mimic human illness as well as
suggest an underlying mechanism involving increased
ROS and superoxide levels.
MnSOD as a Sirt3 deacetylation target that directs
enzymatic detoxification activity
Manganese superoxide dismutase (MnSOD) is one of
the primary mitochondrial antioxidant in a network of
detoxification enzymes that neutralizes the highly
reactive superoxide ions (O2•¯) to less reactive
hydrogen peroxide (H2O2) followed by its immediate
conversion to H2O by catalase and other peroxidases in
the mitochondrial matrix . Superoxide is the by-
product of electron transport chains I and III while they
work inefficiently, and arises as a primary damaging
reagent for mtDNA and
macromolecules [19,23]. ROS, in order of sequential
reduction from O2, include superoxide (O2•¯), hydrogen
peroxide (H2O2), hydroxyl radical (.OH), and organic
peroxides, that are normally produced during respiration
. While low amounts of ROS are natural side
products of various electron transfer reactions and
easily tolerated by the cell, abnormally high levels of
ROS from any number of possible sources induces
oxidative stress and can damage cells by peroxidizing
lipids, and disrupting proteins and nucleic acids [25,26].
Since MnSOD enzymatically scavenges superoxide,
which is increased in cells lacking Sirt3 , it seemed
logical to suggest that cells lacking Sirt3 might have
altered regulation of MnSOD activity.
The balance between the mitochondrial antioxidant
detoxification system and ROS should be finely
maintained while low levels mitochondrial ROS in are
required by cells to modulate normal redox signaling
networks. In addition, excessive amounts of ROS is
believed to shortened life span  and induced age-
carcinogenesis, cardiovascular, and other diseases
[29,30]. While MnSOD-/- mice are neonatal lethal the
MnSOD+/- mice display higher oxidative damage and
incidence of tumor formation [31,32]. Mutations
in SOD2 were associated with human age-related
conditions, such as
www.impactaging.com 103 AGING, February 2011, Vol.3 No.2
disorders, such as cardiomyopathy, neuronal diseases,
and cancer [33-36]. These results clearly demonstrate
the significant role for the aberrant regulation of
MnSOD in age-related illnesses and suggest that
upstream signaling proteins that regulate MnSOD may
also play a role in these pathologies as well.
There is an accumulating evidence that in specific solid
tumors there is a very strong correlative statistically
connection between aging as well as aberrant
mitochondrial ROS regulation [37-39]. In this regard,
the mice lacking Sirt3 appear to be an new in vivo
model to investigate the connection between aging and
carcinogenesis since these mice, at ages greater than 13
months, developed well differentiated ER/PR receptor
positive mammary tumors, which is the subtype of
breast cancer that is most commonly observed in
postmenopausal women . Kim and his colleagues
proposed that increased mitochondrial superoxide level
was one of the major reasons triggering breast tumor
development in the older Sirt3 knockout mice. In
addition to breast tissue, SirT3 deficient mouse
hepatocytes and cardiomyocytes displayed significant
mitochondrial superoxide levels [18,20]. Thus, it has
been proposed that SIRT3 protects against ROS by
enhancing the activity of antioxidant defense system,
suggesting that this protein could be an imperative
mitochondrial fidelity protein in the face of oxidative
stress [18,20,40]. Based on these results our research
group hypothesized that Sirt3 may bind to and regulate
the enzymatic properties of MnSOD that detoxifies
mitochondrial superoxide so as to prevent oxidative
stress and cellular damage .
In this regard, we have recently shown in a manuscript
published in Molecular Cell that MnSOD contains a
reversibly acetylated lysine residue that is deacetylated
by caloric restriction and 36 hours of fasting and
MnSOD . Purified MnSOD was also shown to be
directly deacetylated by recombinant SIRT3 in an in
Figure 1. Proposed model figure describing Sirt3 acetylation and subsequent regulation of MnSOD detoxification
enzymatic activity. Sirt3 is localized into the inner mitochondrial membrane and appears to be activated by agents that
induce oxidative stress, such as ionizing radiation, or changes in cellular nutrient status, such as caloric restriction or fasting.
Our data suggests that MnSOD enzymatic activity is directed by acetylation of lysine 122 following fasting or exposure to
radiation via the activation of Sirt3. Sirt3 has also been shown to regulate the activity of other mitochondrial proteins
including Acetyl‐CoA synthetase 2 (AceCS2) [15,44], glutamate dehydrogenase (GDH) [44,45], long‐chain acyl‐CoA
dehydrogenase (LCAD) , and isocitrate dehydrogenase 2 (Idh2) .
www.impactaging.com 104 AGING, February 2011, Vol.3 No.2
vitro deacetylation assays and re-introduction of the
wild-type, but not a deacetylation null, Sirt3 gene
decreased MnSOD acetylation as well as increased
MnSOD activity. These results strongly suggested that
Sirt3 deacetylation activity directly directs MnSOD
acetylation status as well as its enzymatic detoxification
It was also shown that MnSOD physically interacts with
Sirt3 and lysine 122 is deacetylated by Sirt3, suggesting
that acetylation of this lysine, at least in part, may
regulate MnSOD function. This idea was validated by a
MnSOD mutant that demonstrated increased activity
when lysine 122 was changed to arginine (to mimic the
deacetylated state). MnSODK122-R decreased superoxide
levels in MEFs lacking MnSOD as well as prevented
Infection of MnSODK122-R into MEFs lacking Sirt3 also
decreased cellular superoxide levels and reversed the
tissue culture immortalization
permissive phenotype observed in these primary cells.
These results suggest that MnSOD amino acid K122,
which is conserved in multiple complex and primitive
species, including C. elegans, directs MnSOD
enzymatic detoxification activity as well as plays a role,
at least in part, the damage permissive phenotype
observed in murine cells lacking Sirt3 . Similar
results for the role of Sirt3 regulation of MnSOD via
acetylation has also be shown by the Chen laboratory
 however, this group identified lysines 53 and 89 as
acetylation targets that direct enzymatic function. Thus,
this implies that MnSOD may contain additional
reversible acetyl lysines that determine enzymatic
In this manuscript we also showed livers from the Sirt3
knockout mice exposed to 2 Gy of radiation on two
consecutive days demonstrated an ionizing radiation-
induced damage permissive phenotype. This was
determined by radiation-induced liver periportal to
midzonal hepatocellular swelling, dilation of the
cytoplasm, poorly defined vacuoles, and increased
apoptosis and ROS, specifically ONOO-, a reaction
product of nitric oxide and superoxide . This
histology displays some characteristics similar to, at
least in part, to that observed in microvesicular steatosis
that is associated with mitochondrial dysfunction .
Interestingly, the risk factors for steatosis include
diabetes mellitus, protein malnutrition, and obesity ,
all of which have been associated with abnormalities of
Sirtuin function . These results suggest an
oxidative stress permissive phenotype, including
increase cellular superoxide levels, in liver cells lacking
Sirt3. These results as well as those observed by others
for fatty liver , insulin resistance , and cardiac
of MnSOD-/- MEFs.
hypertrophy [20,21] clearly show that the mice lacking
Sirt3 exhibit a cell damage permissive phenotype for
age-related illnesses and strongly suggest a mechanisms
involving aberrant accumulation of mitochondrial
superoxide levels. Finally, while the data does not
definitively show that the aberrant acetylation a
subsequent regulation of MnSOD is causative in these
pathological processes, these results do make a strong
potential scientific argument for altered regulation of
The results discussed above suggest that loss of a single
mitochondrial protein and the aberrant regulation of the
mitochondrial acetylome signaling network that
responds to metabolic demands and deacetylates
downstream target proteins results in a phenotype
permissive for human illnesses associated with aging.
In this regard, MnSOD as well as several other recently
identified mitochondrial proteins such as acetyl-CoA
synthetase [15,44], glutamate dehydrogenase GDH)
[44,45], long-chain acyl-CoA dehydrogenase (LCAD)
, succinate Dehydrogenase , Ku70 ,
mitochondrial ribosome subunit MRPL10 , and
isocitrate dehydrogenase . These Sirt3 targets all
appear to regulate critical mitochondrial enzymes that
regulate energy metabolism and very strongly suggested
that Sirt3 is a mitochondrial metabolism sensing protein
maintains energy homeostasis responding to specific
nutrient and environmental conditions. As such, we
believe the Sirt3 knockout mice represent a new
paradigm that mechanistically links mitochondrial
metabolism, the acetylome post-translation signaling
network, and age-related disease including ER/PR
breast cancer carcinogenesis, radiation-induced liver
steatosis, fatty liver, insulin resistance, cardiac
hypertrophy, and neurodegenerative diseases.
DG is supported by 1R01CA152601-01 from the NCI,
BC093803 from the DOD, and SPORE P50CA98131.
DRS and MCC were supported by grants from the NIH
and DOE (R01CA133114,
P30CA086862, and DE-SC0000830).
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