Journal of Chemical Neuroanatomy 95 (2019) 43–53

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Journal of Chemical Neuroanatomy

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Review

Mitochondrial SIRT3 and neurodegenerative brain disorders T

Anamika, Archita Khanna, Papia Acharjee, Arup Acharjee, Surendra Kumar Trigun
⁎

Biochemistry Section, Department of Zoology, Institute of Science, Banaras Hindu University Varanasi, 221005, India

ARTICLE INFO ABSTRACT

Keywords: Sirtuins are highly conserved NAD+ dependent class III histone deacetylases and catalyze deacetylation and ADP
Sirtuins ribosylation of a number of non-histone proteins. Since, they require NAD+ for their activity, the cellular level of
SIRT3 Sirtuins represents redox status of the cells and thereby serves as bona fide metabolic stress sensors. Out of seven
Mitochondrial derangement homologues of Sirtuins identified in mammals, SIRT3, 4 & 5 have been found to be localized and active in
Excitotoxicity
mitochondria. During recent past, clusters of protein substrates for SIRT3 have been identified in mitochondria
Neurodegenerative brain disorders
and thereby advocating SIRT3 as the main mitochondrial Sirtuin which could be involved in protecting stress
induced mitochondrial integrity and energy metabolism. As mitochondrial dysfunction underlies the patho-
genesis of almost all neurodegenerative diseases, a role of SIRT3 becomes an arguable speculation in such brain
disorders. Some recent findings demonstrate that SIRT3 over expression could prevent neuronal derangements in
certain in vivo and in vitro models of aging and neurodegenerative brain disorders like; Alzheimer’s disease,
Huntington’s disease, stroke etc. Similarly, loss of SIRT3 has been found to accelerate neurodegeneration in the
brain challenged with excitotoxicity. Therefore, it is argued that SIRT3 could be a relevant target to understand
pathogenesis of neurodegenerative brain disorders. This review is an attempt to summarize recent findings on
(1) the implication of SIRT3 in neurodegenerative brain disorders and (2) whether SIRT3 modulation could
ameliorate neuropathologies in relevant models.

1. Introduction
A protein, first identified in brewer’s yeast S. cerevisiae, was found to
be primarily involved in delaying cell senescence in this organism by
gene silencing mechanisms and it was named as silent information
regulator 2 (SIR2) (Haigis and Sinclair, 2010). Later SIR2 was found to
be a member of an evolutionarily conserved family of proteins, known
as Sirtuins, found in almost all life forms and catalyze NAD+ dependent
protein deacetylation. Notably, a direct link of Sirtuin activity with that
of calorie restriction (CR) and aging in many organisms (Imai et al.,
2000; Lin et al., 2000) strongly advocated about roles of such protein
deacetylases in maintaining normal cellular functions, cell and/or or-
ganism senescence and age-related diseases in mammals.
A rapid progress in Sirtuin research, thereafter, emphasized that
these protein deacetylases target an array of metabolic and cell sig-
naling proteins and thus, act as an important epigenetic regulator of cell
functions. Use of NAD+ for each cycle of their catalytic activity cate-
gorized them as a bona fide metabolic/bioenergetic sensor of the cells
(Berger et al., 2005; Haigis and Sinclair, 2010). Presence of conserved
allosteric sites for activators (resveratrol and related compounds) and
inhibitor (nicotinamide) and identification of many protein modifica-
tion sites make them a target of multimodal regulations as well (Tanno
et al., 2007; Haigis and Sinclair, 2010; Cantó and Auwerx, 2012). In-
deed, these proteins are now described to regulate key cellular pro-
cesses of metabolic adaptations and stress responses and thereby
maintain health and longevity (Haigis and Sinclair, 2010).
Importantly, reports from last decade emphasize that some of the
Sirtuins, SIRT1 and SIRT3 in particular, are expressed in most of the
brain regions (Sidorova-Darmos et al., 2014) and they help maintain
higher order brain functions and protect brain cells from un-
physiological insults and neurodegeneration (Donmez and Outeiro,
2013). Therefore, the present review is organized to first present an
overview on Sirtuin biochemistry in general and then to describe their
roles in maintaining brain functions and neuropathologies. Since, mi-
tochondrial dysfunction underlies the pathogenesis of most of the
neurodegenerative brain disorders; much emphasis has been given on
this mitochondria active deacetylase in the brain.
1.1. Biology of SIRTUINS
As illustrated in Fig. 1, the catalytic deacetylation by all the Sirtuins,
including SIRT3, begins with hydrolysis of the glycosidic bond of NAD+
to generate nicotinamide (NAM) and an ADP-ribose intermediate. This
follows transfer of the acetyl group from a lysine residue of an

⁎
Corresponding author.
E-mail address: sktrigun@gmail.com (S.K. Trigun).

https://doi.org/10.1016/j.jchemneu.2017.11.009
Received 20 June 2017; Received in revised form 16 September 2017; Accepted 8 November 2017
Available online 09 November 2017
0891-0618/ © 2017 Elsevier B.V. All rights reserved.
Anamika et al.
Fig. 1. Protein deacetylation reaction pathway of Sirtuons including SIRT3. The catalytic
reaction of all the Sirtuins is completed in two steps. It starts with cleavage of the NAD+
glycoside to produce NAM and an ADP-ribose which, in the next step, accepts acetate
group transferred from the susceptible lysine residue of an acetylated protein to syn-
thesize 2′-O-acetyl-ADP-ribose and thus leaving behind the substrate protein deacety-
lated. Since cells cannot afford to lose NAD+ after each Sirtuins reaction, they operate an
enzymatic mechanism to reuse NAM, the NAD+ cleavage product, to re-generate NAD+.
NAM is first converted into NMN by the enzyme NAMPT which, subsequently is converted
back to NAD+ by another enzyme, NMNAT.
acetylated protein to the 2′-OH of ADP-ribose intermediate to produce
2′-O-acetyl-ADP-ribose. Thus finally Sirtuins activity ends up with
generating a deacetylated protein, a NAM and a 2′-O-acetyl-ADP-ribose
(Haigis and Guarente, 2006).
Each cycle of the Sirtuin catalyzed reaction consumes one equiva-
lent of NAD+ and thereby likely to swing the NAD+: NADH ratio in the
cells. Thus, the level of the Sirtuins activity is considered to directly
relate with the redox and bioenergetic status of the cell. For example, a
reduced NAD+: NADH ratio becomes inevitable during increased
Sirtuins activity and therefore, mammalian cells have been evolved
with an enzymatic mechanism to regenerate NAD+ from the NAM. As
illustrated in Fig. 1, this happens in two steps: Nampt (Nicotinamide
phosphoribosyltransferase) converts NAM to nicotinamide mono-
nucleotide (NMN) (Revollo et al., 2004). Subsequently, NMNAT (ni-
cotinamide mononucleotide adenyl transferase), an another enzyme,
regenerate NAD+ from NMN (Berger et al., 2005; Haigis and Sinclair,
2010). Such NAD+ dependency of Sirtuins including mitochondrial
SIRT3 qualify them as bona fide bioenerergetic sensors of the cells.
In mammals, seven homologues of sirtuins (SIRT1-7) have so far
been identified sharing a conserved catalytic core domain, however,
with slightly different N and C termini extensions (North and Verdin,
2004). The N terminal extension is responsible for their differential
subcellular localization and substrate specificity whereas, variable C-
termini, as extended region of the catalytic domain, probably con-
tribute in determining reaction specificity of different Sirtuins (North
and Verdin, 2004; Moniot et al., 2012; Flick and Luscher, 2012).
Accordingly, based on the type of reactions they catalyze, these
Sirtuins have conveniently been classified into four classes. Sirtuins
classification and specific structural details is given in Table 1. As
evident from the table data, with the robust deacetylase activity, class I
Sirtuins; SIRT1, SIRT2 & SIRT3, are evident to regulate diversified cell
functions and thus, derive much scientific merit to study class I Sirtuins
as relevant targets to understand metabolic adaptations under normal
and diseased conditions.
Importance of Sirtuins got further highlighted due to their specific
sub-cellular locatizations. As illustrated in Table 2, SIRT1, 6 and 7 are
found in the nucleus and known to regulate expression of many critical
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Journal of Chemical Neuroanatomy 95 (2019) 43–53
Table 1
Biochemical classification of Sirtuins: Catalytic specificity and structural details (Carafa
et al., 2012; Herskovits and Guarente, 2013).
Class Sirtuins Acitvity Structure MW (kDa): AA (Catalytic
domain)
Class I SIRT1 Deacetylase 81.7: 747 (244–498)
SIRT2 41.5: 389 (65–340)
SIRT3 43.6: 399 (139–382)
Class II SIRT4 ADP- ribosyltransferase 35.2: 314 (45–314)
Class III SIRT5 Demalonylase 33.9: 310 (41–309)
Desuccinylase
Deacetylase
Class IV SIRT6 ADP-ribosyltransferase 39.1: 355 (35–274)
SIRT7 Deacetylase () 44.9: 400 (90–331)
genes involved in promoting cell survival by deacetylating an array of
transcription factors (Pillai et al., 2010a). SIRT2 resides in the cyto-
plasm and plays an important role in oxidative stress resistance (Wang
et al., 2007), cell motility and cell division by deacetylating α-tubulin
(North et al., 2003). The Sirtuin isoforms targeted to mitochondria are
SIRT3, 4 and 5. These Sirtuins evidently serve as stress sensors and
modulate the activity of several key mitochondrial proteins to induce
adaptive changes during bioenergetic deficits, ROS insult, apoptosis,
aberrant signal transduction and deranged intermediary metabolism
(Verdin et al., 2010). As evident from a bigger list of protein substrates
(Table 2), SIRT3 could be considered as the main mitochondrial NAD+-
dependent stress responsive protein deacetylase (Verdin et al., 2010).
1.2. Sirtuins in brain
As illustrated in Table 3, out of all the Sirtuins, SIRT1 & SIRT3 re-
present maximum Sirtuins activity in the neurons and are reported to
regulate most of the critical brain functions and thus, considered to be
involved in the pathogenesis of almost all age related and neurode-
generative brain disorders. In the rodent brain, SIRT1 has been the most
studied Sirtuins wherein, it is demonstrated to be mainly expressed in
the neurons (Ramadori et al., 2008). SIRT1 expression has been de-
tected as early as 3 day postnatal mice brain localized in both nucleus
and cytosol whereas, in adult brain, it is predominantly cytosolic (Li
et al., 2008). SIRT1 has been detected in CA1 to CA4 regions of the
hippocampus, basal ganglia circuits (e.g. Substantia nigra), brain stem
(e.g. raphe nucleus) and cerebellum (Zakhary et al., 2010). Brain region
specific differential distribution of this protein deacetylase is also on
record. The expression of SIRT1, at both transcript and protein levels, is
found to be highest in cerebellum, moderate in cortex, hippocampus,
striatum and olfactory bulb and lowest in the spinal cord (Sidorova-
Darmos et al., 2014). Moreover, it was important to note that absence of
SIRT1 could impair cognitive abilities including immediate memory,
classical conditioning and spatial learning (Michán et al., 2010) and
thus suggested a critical role of SIRT1 in maintaining higher order brain
functions and synaptic plasticity including its role in promoting dif-
ferentiation of neuronal progenitor cells (NPCs) (Wang et al., 2011).
Although SIRT1 has been the main Sirtuins target to understand
pathogenesis of many neurological diseases caused due to protein ag-
gregation or due to toxicity of α-synuclein, tau, huntingtin and Aβ
peptide (Duan, 2013), some recent reports do argue for significant roles
of other sirtuins in neurodegeneration (Donmez and Outeiro, 2013).
Since, mitochondrial dysfunction lies at the centre of many neurode-
generative disorders, as listed in Table 3, the SIRT3, primarily active in
neuronal mitochondria, could be considered another hot spot for un-
derstanding pathogenesis and therapeutic strategies against neurode-
generative diseases. Some reports during recent past suggest about a
direct association of SIRT3 deficiency with the induction of certain
classical neurological diseases. For example, SIRT3 deficiency in Hu-
tingtons protein expressing brain cells (Fu et al., 2012), down regula-
tion of SIRT3 in the frontal cortices of APOE4 carrier human brain (Yin
Anamika et al. Journal of Chemical Neuroanatomy 95 (2019) 43–53

Table 2
Subcellular localization, target proteins and cellular/physiological functions known to be regulated by different Sirtuin homologues reported in mammals.

Sirtuins Subcellular location Protein Substrates Functions References

SIRT1 Nuclear p53, FOX03a, Bax, HIF-1α, STAT3, Energy metabolism, differentiation, neuroprotection Haigis and Sinclair, 2010
PGC1α, NFƙB, PPARγ
SIRT2 Cytoplasmic α-tubulin, H4, FOXO Cell cycle regulation North et al., 2003
SIRT3 Mitochondrial matrix LCAD, SDH, GDH, LKB1, NDUFA9, Fatty acid oxidation, amino acids catabolism, TCA cycle, Ahn et al., 2008; Sundaresan et al.,
IDH2, SOD2, FOXO3a, CypD, Ku70, ATP production, mito- protein synthesis ROS homeostasis, 2009; Qiu et al., 2010; Verdin et al.,
p53, MRPL10, PGC1α balance of survival and apoptosis, 2010; Hallows et al., 2011;
SIRT4 Mitochondrial matrix GDH Amino acid catabolism Verdin et al., 2010;
SIRT5 Inner Mitochondrial CPSI Urea Cycle Verdin et al., 2010;
Membrane Du et al., 2011
SIRT6 Nuclear H3K9, H3K56, HIF1α, NFƙB, DNA DNA repair and inflammation Nakagawa and Guarente, 2011; Jiang
polymerase β et al., 2013
SIRT7 Nucleolus RNA pol I, SMAD6, p53 RNA pol I activity Michan and Sinclair, 2007;
Haigis and Sinclair, 2010

et al., 2015a; Ansari et al., 2017), SIRT3 deficiency and increased loss of
dopaminergic neurons in substantia nigra and striatum of MPTP (1-
methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced PD mice (Liu
et al., 2015).
2. SIRT3
SIRT3 has been reported to regulate almost every aspect of mi-
tochondrial functions like; mitochondrial biogenesis and dynamics,
ROS metabolism, ATP production and maintenance of mitochondrial
integrity (Bause and Haigis 2013). In addition, SIRT3 is directly linked
to the human longevity also (Kong et al., 2010; Brown et al., 2013;
Kincaid & Bossy-Wetzel, 2013; Ansari et al., 2017). Though, SIRT3
Knockout mice exhibited a normal physiology under normal condition
but under stress condition or with aging, these animals develop age-
related diseases at an accelerated pace (Lombard and Zwaans, 2014;
McDonnell et al., 2015). Similarly, SIRT3 knockout animals have been
shown to have increased acetylation of mitochondrial proteins (Fritz
et al., 2012; Hebert et al., 2013) and altered mitochondrial metabolism
like, fatty acid oxidation, urea cycle defects, declined ATP production
and increased oxidative damage from ROS (Ahn et al., 2008; Qiu et al.,
2010; Hallows et al., 2011). Involvement of SIRT3 in metabolic adap-
tations of mitochondria against various metabolic disorders, cardiac
dysfunction, cancer, aging and neurological disorder have been ex-
amined by various groups as well (Lombard et al., 2007; Someya et al.,
2007; Anderson et al., 2009; Nicholls, 2009). Moreover, it is becoming
clearer that SIRT3 could act as a potential therapeutic target with re-
spect to mitochondrial dysfunction led neurological disorders.
This is further supported by the fact that the level of SIRT3 changes
according to the nutrient status of the cell in a tissue specific manner
(Hirschey et al., 2011; Hebert et al., 2013). It is expressed maximally in
metabolically active tissues like brain, heart, kidney, liver, brown adi-
pose tissue and skeletal muscles (Onyango et al., 2002; Schwer et al.,
2002; Shi et al., 2005). In particular, SIRT3 expression in the adult
brain shows similar pattern in cortex, hippocampus, striatum, spinal
cord and brain stem and at modestly lower levels in the cerebellum
(Sidorova-Darmos et al., 2014). However, SIRT3 expression has been
found to be declined significantly in the cortex and hippocampus of
aging rats (Braidy et al., 2015) and thus, indicating its significant role in
age-associated brain disorders.
Therefore, to highlight mechanistic aspects about neuroprotective
roles of SIRT3, in the present review the structural and regulatory as-
pects of this deacetylase have been given due space followed by sum-
marizing the current status about how SIRT3 could be implicated in
neuropathogenesis and neuroprotection.
2.1. SIRT3 structure and organelle targeting
Like other sirtuins, SIRT3 also utilizes NAD+ as the main cofactor
for its activity and hence, its activity directly relates with the increased
NAD+/NADH ratio in the cells (Haigis and Sinclair, 2010; Kincaid and
Bossy-Wetzel, 2013). Furthermore, SIRT3 also contains a conserved
core domain for the binding of NAD+ and the protein substrate.
Schematic arrangement of different functional and regulatory domains
of a full length SIRT3 has been illustrated in Fig. 2. A conserved cata-
lytic core domain of ∼275 aa is consisting of a large NAD+ binding
Rossmann fold made up of several inverted classical open α/β struc-
tures followed by a substrate binding site and a groove of several loops
forming a connecting cleft between NAD+ and acetylated peptide
substrate (Carafa et al., 2012; Moniot et al., 2012). Many regulatory
sites including Zn2+ binding domains have also been reported in SIRT3
(Min et al., 2013). Importantly, the amino and carboxy terminal ex-
tensions autoregulate enzymatic activity of this protein, e.g. C terminal
extended loop region is known to interact with the NAD+ binding
pocket of large domain while N terminal extension help maintains
substrate specificity (North and Verdin, 2004).
Despite some initial controversies about subcellular localization of
SIRT3, majority of evidences suggest mitochondrial matrix as primary

Table 3
Sirtuins in Brain: Brain cellular specificity and implication in age related neurodegenerative disorder.

SIRTUINS Brain cell specificity Age Related Brain Disorder References

SIRT1 Neurons and astrocyte AD, PD, HD, ALS, Wallerian degeneration, Multiple Duan 2013; Braidy et al., 2015
sclerosis
SIRT2 Myelin producing cells; Oligodendrocytes and schwann ↓Gliomas; Its inhibition prevents AD, PD, HD Michan and Sinclair, 2007; de Oliveira et al.,
cells 2012
SIRT3 Neurons, rare in gliocytes AD,PD,HD, ALS, ARHL Herskovits and Guarente, 2013; Huang et al.,
2016
SIRT4 Detected in Glial cells (astrocytes) Unknown Komlos et al., 2013
SIRT5 Detected in neuron and astrocyte Unknown Braidy et al., 2015
SIRT6 Neuron and astrocyte AD Braidy et al., 2015
Kaluski et al., 2017
SIRT7 Detected in neuron and astrocyte Unknown Braidy et al., 2015

45
Anamika et al.
sites are also located within the catalytic domain. The C terminal extended region is known to interact with the NAD binding pocket of the catalytic domain while N terminal extension is
known to help maintain substrate specificity.
site of SIRT3 activity (Lombard et al., 2007; Cooper and Spelbrink,
2008; Sundaresan et al., 2008). Nonetheless, short length and full
length SIRT3, found in humans and mice, as two different isoforms,
appear to be differentially distributed in a tissue-specific manner (Scher
and Vaquero, 2007). As depicted in Fig. 2, SIRT3 is synthesized as a
44 kDa full length inactive protein with a stretch of N terminal 142 aa,
The first 25 aa sequences act as mitochondrial localizing sequences
(MLS) (Onyango et al., 2002). After this protein enters into the mi-
tochondrion, the MLS stretch is removed by a mitochondrial matrix
peptidase at a conserved site around 142 aa resulting into generation of
an active 28 kDa short form of SIRT3 (Schwer et al., 2002; Scher and
Vaquero, 2007). It has been reported that this N-terminal additional
stretch might regulate the access of protein substrates to the active site
of the enzyme (Schlicker et al., 2008) and thus, imparting its functional
inactivation before it reaches to the mitochondrial matrix. Additionally,
high-resolution mass spectrometry-based phosphor-proteome analysis
has identified six phosphorylated serine residues between positions
101–118 closer to the mitochondrial cleavage site (Olsen et al., 2010)
and thus, suggesting for phosphorylation status dependent prevention
of substrate binding to SIRT3 active site before its mitochondrial entry
(Flick and Lüscher, 2012).
2.2. SIRT3 and mitochondrial integrity
It is known from ages that calorie restriction (CR), fasting or ex-
ercise boost cellular repair mechanism and endorse healthy lifespan.
During recent past, some studies have shown that CR promotes dea-
cetylation of many mitochondrial proteins by upregulating SIRT3 ex-
pression resulting into increased oxidative phosphorylation and indu-
cing multimodal adaptations in mitochondrial functions (Lombard
et al., 2007; Palacios et al., 2009). Mitochondria are the primary site of
generating ROS and thus become immediate target of oxidative da-
mage. SIRT3 is now emerging as an important regulator of mitochon-
drial antioxidant defense mechanism (Chen et al., 2014) and it does so
by employing more than one mechanisms. SIRT3 mediated activation of
mitochondrial Mn-SOD is considered to be the most plausible one (Qiu
et al., 2010). It is now becoming clearer that CR and ROS imbalance vis
a vis SIRT3 level are mutual in maintaining mitochondrial structure and
functions.
As illustrated in Fig. 3, the bioenergetic deficit reflected by in-
creased AMP/ATP ratio activates AMPK/CREB signaling to induce
SIRT3 expression by involving PGC-1α (peroxisome- proliferator acti-
vated receptor gamma co activator 1-alpha) and nuclear respiratory
factor 2 (NRF2)/estrogen related receptor α (ERRα) trans activation
mechanisms (Kong et al., 2010; Giralt et al., 2011; Satterstrom et al.,
2015; Ansari et al., 2017). In addition to its role in enhancing nuclear
transcription of ROS detoxification genes (Shi et al., 2005) in a feed-
back loop mechanism, after it enters into mitochondria, SIRT3
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Journal of Chemical Neuroanatomy 95 (2019) 43–53
Fig. 2. SIRT3 functional domains: SIRT3 is synthe-
sized as a 44 kDa protein and remains inactive due to
the presence of additional N terminal sequences. The
first 25 aa N-terminal sequences serve as MLS which,
after entry into mitochondria, gets cleaved by a mi-
tochondrial matrix peptidase at a conserved site
around 142 aa to generate an active 28 kDa mi-
tochondria active SIRT3. A stretch between positions
101–118 is reported to contain ∼6 ser phosphor-
ylation sites which are speculated to prevent sub-
strate binding to SIRT3 in a phosphorylation status
dependent manner before it gets transported to the
organelle. A catalytic core domain of ∼275 aa is
comprised of one NAD+ binding Rossmann fold, a
substrate protein binding site and a groove of con-
necting cleft between these two substrate binding
sites. Many regulatory sites including Zn2+ binding
+
evidently promotes mitochondrial biogenesis and ROS detoxification by
deacetylating many protein substrates. As an immediate action, SIRT3
deacetylates Mn-SOD and increases its activity to dismutate oxygen free
radicals. Also, SIRT3 protects cells during oxidative stress by preventing
mPTP (mitochondrial permeability transition pore) opening via deac-
tivating Cyclophilin D (Cyp D) which blocks the release of GSH and cyt
c and thereby prevents cell apoptosis (Bause and Haigis, 2013). In ad-
dition, SIRT3 is also known to deacetylate FOXO3a and facilitates its
nuclear translocation which in turn accounts for increased transcription
of the antioxidant enzymes (Jacobs et al., 2008; Tseng et al., 2013).
Furthermore, PGC-1α is known as a primary regulator of genes in-
volved in mitochondrial biogenesis, metabolism, effective ROS meta-
bolism and stress responses (Herzig et al., 2001; Yoon et al., 2001;
Palacios et al., 2009). It has been described that PGC-1α, arbitrated by
ERRα, stimulates SIRT3 expression by binding to the SIRT3 promoter
region (Kong et al., 2010; Giralt et al., 2011; Ansari et al., 2017).
Satterstrom et al. (2015) proposed that NRF-2 (Nuclear Respiratory
Factor-2) could be a novel regulator of SIRT3 expression. Notably, NRF-
2 is already known to be co-activated by PGC-1α, leading towards en-
hanced expression of its target genes (Mootha et al., 2004; Baldelli
et al., 2013). Intriguingly, SIRT3, in turn, stimulates PGC-1α expression
involving CREB and AMPK feedback loop (Shi et al., 2005; Palacios
et al., 2009; Pillai et al., 2010b). Taking together, SIRT3 adapts more
than one mechanism to protect mitochondria under metabolic stress
challenges.
2.3. SIRT3 and energy metabolism
In general, SIRT3 is activated with increased NAD+/NADH ratio
and regulate complex interactions between metabolic pathways in a
multimodal way. SIRT3 is reported to up regulate TCA cycle by acti-
vating PDH (pyruvate dehydrogenase complex), the first enzyme that
catalyzes pyruvate entry into oxidative energy production pathway.
And it does so mainly by deacetylating E1α subunit (Jing et al., 2013).
In addition, it targets almost all critical TCA cycle enzymes (Schwer and
Verdin, 2008) and has been described to physically associate with and
deacetylate NADH dehydrogenase (ubiquinone) 1 α sub complex 9
(NDUFA9) (Ahn et al., 2008; Lombard et al., 2011). SIRT3 also interacts
with 2 subunit of Fo-F1 ATP synthase leading to deacetylation of alpha
and OSCP subunits (Law et al., 2009; Duan, 2013). In addition, SIRT3 is
likely to regulate expression of some of the sub units of complex IV. It
has been reported that PGC-1α induced expression of complex IV sub-
units is decreased in SIRT3 knockdown condition (Bause and Haigis
et al., 2013). Thus, it is evident that SIRT3 activity critically associates
with the mitochondrial ATP synthesizing machinery (Fig. 3).
SIRT3 is also involved in activating alternate energy pathways like,
fatty acids oxidation. In fact SIRT3 deficient mice are reported to have
reduced ATP level, defect in thermogenesis and hypoglycemia during
Anamika et al.
starvation (Hirschey et al., 2010). SIRT3 deacetylates and activates long
chain acyl CoA dehydrogenase and 3-Hydroxy-3-Methylglutaryl-CoA
Synthase 2 (HMGCS2) and thus promotes utilization of fat as gluco-
neogenic source (Shimazu et al., 2010). Also, SIRT3 promotes gluco-
neogenesis from amino acids by deacetylating and activating glutamate
dehydrogenase (GDH) that converts glutamate into the TCA cycle in-
termediate α-ketoglutarate (Schlicker et al., 2008). SIRT3 also aug-
ments glycolysis by deacetylating Cyclophilin D (Cyp D) which on one
hand keeps hexokinase II inactive and on the other hand prevents its
association with ANT and thereby, blocks mPTP formation (Shulga
et al., 2010).
2.4. Exogenous modulation of SIRT3
Though information is limited about SIRT3 specific modulators
during diseased conditions, some studies describe that resveratrol, a
polyphenolic compound and a known activator of SIRT1, could also
activate SIRT3 (Schirmer et al., 2012). In particular, a dimer of this
compound, a trans-(−)-є-Viniferine, was found to show strong neuro-
protective effects by activating SIRT3 (Fu et al., 2012). Another
bioactive compound, roxylin A, was demonstrated to activate SIRT3 in
human breast cell carcinoma (Wei et al., 2013). Rhamnetin, an o-me-
thylated flavonoid and Honokiol, derived from the bark of magnolia
trees, also showed cardio protective effects by activating SIRT3 (Park
et al., 2014; Pillai et al., 2015).
So far SIRT3 inhibitors are concerned, apart from the NAM, a known
noncompetitive inhibitor of the Sirtuin family enzymes, 5-amino-2
phenyl-benzoxazole have been reported as a novel and specific SIRT3
inhibitor (Chen et al., 2014). These findings, thus, do argue that SIRT3
could be a relevant candidate to undergo modulation by exogenous
factors including natural compounds in the conditions of brain disorder.
Indeed, regulation of SIRT3 activity by exogenous compounds could be
an important issue of future research.
3. SIRT3 and excitotoxicity
Excitotoxicity refers to the prolonged activation of the excitatory
amino acid receptors in the brain leading to neuronal damage or death
(Lipton, 2008; Vincent and Mulle, 2009). Glutamate is the principle
excitatory neurotransmitter involved in regulating synaptic plasticity,
learning, memory and other cognitive functions. However, when pro-
duced in excess, it may develop a condition of neuro-excitotoxicity in
the post synaptic neurons. Glutamate acts through two major classes of
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Journal of Chemical Neuroanatomy 95 (2019) 43–53
Fig. 3. SIRT3 and mitochondrial integrity: Though complete signaling
cascades of the mitochondrial SIRT3 regulation remain unexplored,
based on some recent evidences, it is suggested that increased AMP/
ATP ratio, as a marker of bioenergetic deficit, could activate AMPK/
CREB signaling resulting into induction of SIRT3 expression by trans
activation of PGC-1α and NRF2/ERRα. After SIRT3 enters into mi-
tochondria, it is known to promote mitochondrial ROS detoxification
by deacetylating many proteins; including Mn-SOD, most of the TCA
cycle enzymes, ETS assemblies and Fo-F1 ATPase subunits, resulting
into increased rate of oxidative phosphorylation. It also inhibits mPTP
opening via deactivating Cyp D which blocks the release of GSH and
cyt c and thereby prevents cell apoptosis. In addition, SIRT3 is known
to deacetylate mitochondrial FOXO3a and facilitates its nuclear
translocation for enhanced transcription of the antioxidant enzymes.
In addition, SIRT3 is also found to activate alternate energy pathways
like, fatty acids oxidation and lactate utilization.
post synaptic membrane receptors; Metabotropic (mGlu 1–5) and io-
notropic receptors (NMDA, AMPA and Kainate receptor). Under normal
physiological conditions, glutamate released into the synaptic cleft
binds to the post synaptic NMDA receptor resulting into release of
Mg2+ blockage and opening of the Ca2+ channel and thereby initiating
Ca2+ dependent intracellular signaling (Spandou et al., 2007; Chen and
Lipton, 2006). AMPA receptors are usually co-expressed with the
NMDA receptors and they jointly process the synaptic functions like;
potentiation, learning and memory & excitotoxicity. Prolonged depo-
larization of the postsynaptic neurons is associated with the deranged
glutamatergic activity which in turn is likely to induce excitotoxic
neuronal derangement in a variety of neurodegenerative diseases such
as stroke, Alzheimer’s disease and Parkinson’s disease (Nicholas and
Rothstein, 2006).
Fig. 4 illustrates the most plausible neurochemical events that ul-
timately converge at neuronal mitochondria to induce excitotoxicity led
neurodegeneration. The probable role of mitochondrial SIRT3 in neu-
rodegeneration is an evolving concept backed up by some recent re-
ports, using neuronal cell culture model, that describe prevention of
excitotoxicity in the SIRT3 over expressing neuronal cells (Kim et al.,
2011; Han et al., 2014). This goes in line with some earlier reports as
well which described the role of SIRT3 in maintaining almost every
aspects of mitochondrial function like, energy metabolism, biogenesis
(Shi et al., 2005; Ahn et al., 2008) and protection from oxidative stress
led induction of cell death mechanisms (Sundaresan et al., 2009).
Excitotoxicity associated with glutamatergic system mainly involves
increased Ca2+ influx that activates neuronal nitric oxide synthase
(nNOS) to produce excess of NO and other RNS (reactive nitrogen
species). This in turn may adapt more than one mechanisms like; via
altered NO signaling and/or by directly affecting mitochondrial bio-
chemistry for enhanced ROS production and declined energy status of
the organelle. Together, such aberrant mitochondrial metabolism is
considered to open mPTP leading into cytochrome c release and in-
duction of apoptosis and thus drive the cell to undergo death process
(Lipton, 2008; Lee et al., 2009; Nicholls, 2009). Moreover, as depicted
in Fig. 4 and as described explicitly in the previous text (2.3), all such
mitochondrial derangements could be prevented due to over expression
and sustained activity of SIRT3. Thus, it is speculated that during glu-
tamate excitotoxicity, neuronal cell mitochondria might be challenged
with a declined level of SIRT3 as well.
To bring SIRT3 level down, the excitotoxic cells might adapt two
mechanisms; one, the Ca2+ load dependent altered NO signaling may
significantly affect nuclear activity responsible to transcribe SIRT3 and/
Anamika et al.
or the mitochondrial transport of the SIRT3 protein. Second, the altered
NO signaling and cumulative RNS & ROS load in mitochondria together
may decline SIRT3 activity and thereby depriving mitochondria from its
endogenous protection mechanisms. Although, to delineate the me-
chanism by which glutamate excitotoxicity declines SIRT3 activity is a
relevant hot spot for future research, some reports do suggest that over
expression and activation of SIRT3 could protect neurons from under-
going neurodegenerative changes (Kim et al., 2011; Fu et al., 2012; Han
et al., 2014).
Importantly, some reports from recent past, do advocate that neu-
ronal excitotoxicity constitutes a common neurochemical event asso-
ciated with pathogenesis of most of the neurodegenerative brain dis-
orders and with the brain dysfunctions developed due to neuro-
physiological challenges. The most important ones are; Alzheimer’s
disease, Parkinson’s disease, Huntington’s disease, ALS, stroke etc
(Raymond et al., 2011; Cozzolino and Carrì, 2012; Salvatore et al.,
2012; Ong et al., 2013; Kalogeris et al., 2014; Prentice et al., 2015) and
metabolic brain disorders like hepatic encephalopathy (HE) (Singh and
Trigun, 2014; Mondal and Trigun, 2015). Therefore, for clarity about
roles of SIRT3 in the pathogenesis of a specific brain disorder and for
SIRT3 associated different neuronal/molecular markers and substrates,
the text on SIRT3 and common neurodegenerative brain disorders are
being summarized in a disease specific manner (Fig. 4).
3.1. SIRT3 and Alzheimer’s disease
Alzheimer’s disease (AD) is a complex, late-onset, progressive neu-
rodegenerative disorder associated with memory impairment and se-
vere dementia (Farooqui, 2010). AD is characterized by accumulation
of amyloid β peptide (Aβ) neuritic plaques, neurofibrillary tangles,
synaptic failure and mitochondrial dysfunction. Although the under-
lying molecular mechanism for AD pathogenesis is not clearly eluci-
dated, but it is believed that Aβ mediated oxidative stress, induction of
neuroinflammation and abnormal glutamate metabolism could be im-
plicated in onset and progression of this disease (Kontush, 2001;
Butterfield, 2002).
AD is an example of slow excitotoxicity (Ong et al., 2013) where
NMDA receptor overactivation is found to be in tonic rather than in
phasic manner which allows glutamate to become neurotoxic at con-
centrations that normally shows no toxicity (Putcha et al., 2011). Also,
mitochondrial dysfunction associated with AD involves Aβ entry into
the mitochondria leading to disruption of ETC, generation of ROS and
decreased ATP production (Mungarro-Menchaca et al., 2002; Manczak
et al., 2006). Taking together, all these precipitating events either ori-
ginate from mitochondria and/or converge to derange mitochondrial
48
Journal of Chemical Neuroanatomy 95 (2019) 43–53
Fig. 4. SIRT3, excitotoxicity and neurodegeneration: Glutamatergic
excitotoxicity gets induced mainly due to over activation of NMDAR
at postsynaptic neurons. The resultant influx of Ca2+ is known to
activate nNOS in those neurons, which in turn may adapt more than
one mechanism of NO dependent alterations in neuronal biochem-
istry. Over production of NO in combination with ROS load has been
considered a common pathogenic mechanism of most of the neuro-
degenerative brain disorders. Since neurodegeneration finally begins
due to mitochondrial dysfunction led apoptosis, as depicted in Fig. 3
about SIRT3 dependent prevention of mitochondrial derangement, it
is argued that SIRT3 could also play a significant role in the patho-
physiology of neurodegeneration. Though this aspect needs to be ex-
plored in detail, based on some recent reports, it is speculated that
NMDAR over activation induced nNOS activation could either affect
nuclear mechanism to decline SIRT3 level or could directly, via NO &
ROS interaction, may decrease SIRT3 activity. Since SIRT3 activity
correlates with preventing events leading towards mPTP opening,
cytochrome c release and induction of apoptosis, it is argued that
SIRT3 either alone or in combination with enhanced RNS & ROS load,
might be implicated in the pathogenesis of the neurodegenerative
brain disorders. The argument gets support from some findings that
describe that over expression and activation of SIRT3 could protect
neurons from undergoing neurodegenerative changes.
function. Thus, strongly advocate about signficant roles of SIRT3 in the
pathogenesis of AD.
Indeed some studies report roles of SIRT3 in AD at different stages of
the disease progression. For example, in a primary cortical neurons
model, neurons were induced to undergo apoptosis after treatment with
beta-amyloid (Aβ) in a manner similar to the Alzheimer’s disease (AD).
However, co-treatment with pituitary adenylate cyclase-activating
polypeptide (PACAP) could rescue these neurons mainly by upregu-
lating SIRT3 expression (Han et al., 2014). Also, the PACAP mediated
neuroprotective effect was found to be lost in the condition of SIRT3
knocked down by shRNA in primary cultured neurons (Han et al.,
2014). Furthermore, SIRT3 overexpression has been reported to confer
resistance against oxidative stress and thereby extended neuronal
longevity in primary hippocampal cultures (Weir et al., 2012). Apoli-
poprotein E4 (APOE4) is a major genetic factor associated with late-
onset of AD and it has been reported that SIRT3 is down regulated in
the frontal cortices of APOE4 carrier human brain as compared to the
non-carrier individuals (Yin et al., 2015a; Ansari et al., 2017). Yin et al.
(2015a) have further proposed that SIRT3 level may aid in the diagnosis
of AD.
3.2. SIRT3 and Huntington’s disease
Huntington’s disease (HD) is an inherited, autosomal dominant
neurodegenerative disorder characterized by cognitive dysfunction, loss
of coordination and motor functions. It is caused when the gene for the
huntingtin (Htt) protein, located at 4p16.3, shows an expansion of CAG
repeat that codes for a stretch of glutamine residues, affecting the
protein conformation resulting into aggregation of the mutant Htt in
nucleus and cytoplasm of the affected neurons (Arrasate and
Finkbeiner, 2012). Normal expression of Htt is reported throughout the
body and is required for gene transcription, protein trafficking and
mitochondrial function (Arrasate and Finkbeiner, 2012). But the mu-
tant Htt (mHtt) in the brain, particularly in the caudate-putamen
(striatum) and cortex, leads to neurodegeneration by implicating in-
creased glutamatergic signaling and mitochondrial dysfunction in the
corticostriatal neurons (Raymond et al., 2011).
Notably, cells expressing mHTT have been reported to have de-
clined SIRT3 levels. This reduced SIRT3 activity levels was recovered
after ε-viniferin, a stilbene resveratrol dimer, activation of SIRT3 (Fu
et al., 2012). This SIRT3 activator increases SIRT3 protein level and
activates AMPK by SIRT3-dependent deacetylation of AMPK kinase.
Also it activates liver kinase B1 (LKB1), also known as serine/threonine
kinase 11 (STK11), which in turn enhances PGC-1α level and promotes
mitochondrial biogenesis, electron transport activity, ROS
Anamika et al.
detoxification mechanisms and preserves NAD+/NADH ratio in mHtt
cells (Fu et al., 2012). SIRT3 also directly interacts with SOD2 and
enhances its antioxidant activity. This SIRT3 mediated neuroprotective
role of viniferin was confirmed by siRNA induced SIRT3 knockdown in
mHtt expressing striatal cell culture (Fu et al., 2012; Herskovits and
Guarente, 2013).
3.3. SIRT3 and Parkinson’s disease
PD is an age related movement disorder causing tremor, rigidity,
bradykinesia and postural instability resulting from degeneration of the
dopaminergic neurons within the basal ganglia circuitry, specifically
the substantia nigra pars compacta (SNpc) and accumulation of Lewy
bodies (inclusions that contain α-synuclein and ubiquitin) in the cyto-
plasm (Blesa et al., 2012). The basal ganglion receives two major glu-
tamatergic innervations: from the subthalamic nucleus (STN), the only
excitatory nucleus of the circuit, and the motor cortex. SNpc receives
secondary Glutamatergic projection from amygdala and laterodorsal
tegmental nuclei (Misgeld, 2004).
There are evidences that suggest glutamate excitotoxicity as well
during altered neurotransmitter function in PD, e.g, changes in the
glutamate transporters (Raju et al., 2008; Salvatore et al., 2012) as well
as altered subunit composition and phosphorylation pattern of
NMDARs (Dunah et al., 2000; Xu et al., 2012) in the basal ganglia of
different animal models of PD. Importantly, these changes varied ac-
cording to the degree of striatal denervation and loss of endogenous
dopamine (Ambrosi et al., 2014). The vulnerability of dopaminergic
neurons may be contributed by glutamatergic pathways that associate
with the disruption of mitochondrial and bioenergetic homeostasis,
compromised antioxidant defense and deranged proteolytic machinery
(Ambrosi et al., 2014).
Since SIRT3 is involved in regulating ROS balance and ATP pro-
duction and imbalance of these two factors act as key mediators of
neuronal injury during neurodegenerative diseases, studies on the role
SIRT3 in PD pathogenesis derive much scientific merit. Some of the
studies demonstrated that absence of SIRT3 does not elicit anxiety/
depression like behavior and motor dysfunctions, but its deficiency did
aggravate dopaminergic neuronal loss in the substantia nigra pars
compacta and striatum of MPTP (1-methyl-4-phenyl-1,2,3,6-tetra-
hydropyridine) induced PD mice (Liu et al., 2015). MPTP treatment
caused reduced mitochondrial ROS defense capacity with decreased
SOD2 and GPx expression, however, their expression levels were found
to be further reduced in the absence of SIRT3 (Liu et al., 2015). A si-
milar study demonstrated that SIRT3 plays neuroprotective role in ro-
tenone-induced PD cell model wherein, SIRT3 knockout aggravated
SOD and GSH reduction, loss of mitochondrial membrane potential and
worsened rotenone induced cells death. On the other hand, SIRT3 over
expression could rescue the cells from α-synuclein accumulation, re-
duced antioxidant defense by increasing SOD and GSH level and
thereby preventing derangement of mitochondrial membrane potential
(Zhang et al., 2016a).
3.4. SIRT3 and amyotropic lateral sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease
characterized by progressive loss of upper motor neurons in the cortex
and also lower motor neurons in the brainstem and spinal cord. The
selective loss of neurons results in progressive paresis of bulbar, re-
spiratory and limb muscles without dilapidating sensory and cognitive
functions (Van Damme et al., 2005). ALS is a complex multi-factorial
syndrome which is found to be associated with RNA dysregulation,
protein misfolding, oxidative damage, defective axonal transport, mi-
tochondrial dysfunction and excitotoxicity (Cozzolino and Carrì, 2012).
The deleterious glutamatergic signaling during ALS is evident from the
electrophysiological study demonstrating alterations in the cortical and
spinal neurons (Eisen, 2009). Also, Riluzole, the only effective drug in
49
Journal of Chemical Neuroanatomy 95 (2019) 43–53
ALS, effectively slows down the disease progression and prolongs sur-
vival by inhibiting glutamate release and its receptor (Lacomblez et al.,
1996).
Involvement of altered mitochondrial function during ALS patho-
genesis is evident from the mutant SOD1 accumulation in the ALS pa-
tients (Cozzolino and Carrì, 2012; Tan et al., 2014). The role of SIRT3 in
preserving mitochondrial function was demonstrated against mi-
tochondrial fragmentation led neuronal damage in spinal cord motor
neurons transfected with ALS-typical mutant G93A- SOD1 (Song et al.,
2013). Another instance of SIRT3 modulation in ALS was recorded
when the primary astrocytes from G93A-SOD1 transgenic mice induced
motor neuron death in co-culture but this effect was found to be de-
clined due to the co-culture of the motor neurons with the astrocytes
which over expressed SIRT3 (Harlan et al., 2016).
3.5. SIRT3 and stroke
Stroke is a neurological disorder which occurs due to the neuronal
loss resulting from interrupted blood supply to brain and ultimately
depriving brain from oxygen and glucose supply. Ischemic stroke is a
complex entity and one of the leading causes of disability and death
worldwide (Prabhakaran et al., 2015). Although the exact pathological
mechanism remains intangible, glutamate mediated excitotoxicity is
believed to play a central role in cerebral hypoxia and ischemia led
neuronal death (Chen et al., 2011). Evidences suggest that cerebral
ischemia causes increased glutamate release in the intracerebral sy-
napses and thereby elicits prolonged activation of postsynaptic neurons
accompanied with oxidative stress, energy deficit and calcium overload
leading to mitochondrial dysfunction and induction of apoptotic sig-
naling cascade (Bosley et al., 1983; Dawson et al., 2000; Kalogeris et al.,
2014).
Mitochondrial involvement in the stroke pathology has been de-
scribed by various studies; however, information is scanty on the role of
SIRT3 in this disease. Moreover, a recent report on the neuroprotective
effects of SIRT3 in stroke by Yin et al. (2015b) provides a strong support
in this context. They found that administration of ketones; beta-hy-
droxybutyrate (BHB) and acetoacetate (ACA) to mice 30 min after
ischemia induced SIRT3-FoxO3a-SOD2 pathway which in turn could
reduce oxidative stress and enhanced ETC Complex I activity resulting
into reduction of infarct volume and improvement of neurological
functions. The protective effect of SIRT3 is also demonstrated in oxygen
and glucose deprivation (OGD) model of neuronal ischemia where over
expression of SIRT3 through lentivirus transfection not only resulted in
declined oxidative stress associated with OGD but also could maintain
mitochondrial functions and mitochondrial membrane potential
through modulating AMPK-mTOR pathway (Dai et al., 2017). Ad-
ditionally, SIRT3 has been found to be involved in suppressing neu-
roinflammation in post cardiopulmonary bypass and ischemic re-
perfusion cerebral injury. Report describes that SIRT3 knockdown is
associated with worsen neurological function due to the increased
cerebral level of active acetylated form of NLRP3 and NFƙB along with
declined activity of MnSOD during such cerebral injury (Zhang et al.,
2016b). Taking together, these findings strongly argue for the detailed
studies on identification of other key players of such SIRT3 dependent
manifestation of stroke pathology.
3.6. SIRT3 and hepatic encephalopathy: an evolving concept
Unlike other neurodegenerative diseases, hepatic encephalopathy
(HE) is not an age related brain disorder. HE is a metabolic brain dis-
order characterized by variable degree of motor and cognitive deficits
due to liver dysfunction (Bajaj et al., 2009; Felipo et al., 2012; Singh
et al., 2014). The pathology of this neuropsychiatric complication is
associated with peripheral inflammation and hyperammonemia led
glutamate excitotoxicity by over activating NMDAR (Monfort et al.,
2002; Cauli et al., 2002; Mondal and Trigun 2014). Over activation of
Anamika et al.
the receptor leads to delayed opening of the ion channel and increased
influx of Ca2+ which allows activation of calcium-dependent signaling
cascades wherein, nNOS acts as a major mediator of deranged neuronal
functions developed due to NMDAR over activation (Singh and Trigun,
2010; Mondal and Trigun, 2015).
Importantly, at downstream level, NMDAR over activation also re-
sults into mitochondrial dysfunction, bioenergetic deficit, oxidative and
nitrosative stresses (Singh et al., 2008; Singh and Trigun, 2010; Felipo
et al., 2012; Mehrotra and Trigun, 2012; Singh et al., 2014). Though
information is lacking on implication of Sirtuins in the pathogenesis of
HE, however, a recent report, on the protective effects of resveratrol, a
known sirtuins activator, against the hyperammonemia induced pro-
inflammatory and pro-apoptotic conditions in brain of the HE rats
(Khanna and Trigun, 2016), does provide strength for a role of Sirtuins
in HE pathogenesis. Thus, since SIRT3 is known to maintain mi-
tochondrial integrity, it is arguable to speculate a significant role of this
mitochondrial Sirtuin in the pathogenesis of HE. Accordingly, SIRT3
may also be speculated as a relevant therapeutic target against such
excitotoxic brain disorders.
4. Concluding remarks
Sirtuins, by deacylating an array of non-histone proteins, constitute
an important aspect of epigenetic regulation of metabolic integrity, cell
survival and cellular homeaostasis in normal and in diseased condi-
tions. As such it has now invited much attention as a central molecule of
concern for therapeutic management of many crucial human ailments
like, cancer and cardio vascular diseases. Moreover, implication of
Sirtuins in the pathogenesis of neurological complications is a relatively
less explored area. Nonetheless, the information available so far, from
the recent researches, suggest that this class of deacetylases are likely to
play crucial roles in protecting neurons from undergoing neurochemical
derangements during most of the brain disorders developed due to
neuro-excitotoxicity led neurodegeneration. Though much of informa-
tion available so far have been derived from in vitro and/or primary
neuronal culture models, but as described in a review from Herskovits
and Guarente (2013), it is evident that certain specific Sirtuins do
modulate even some signaling steps of the AD, PD and Hutington’s
disease pathogenesis. Additionally, it is now being realized that there is
a need to target organelle specific Sirtuins homologues for under-
standing brain disorder pathogenesis and examining them as relevant
therapeutic target.
Out of the 7 Sirtuins identified, SIRT3, due to its location and ac-
tivity in mitochondria, has now become a point of neurological con-
cern. This is because, most of the neurodegenerative brain disorders
implicate neuro-excitotoxicity whose pathogenic mechanisms either
originate from and/or converge at mitochondrial derangements in the
post synaptic neurons challenged with excessive excitatory activity.
Since, SIRT3 is now considered critical in maintaining mitochondrial
integrity; it deserves special focus for understanding pathogenesis of the
neurodegenerative brain disorders and hence evaluating it as a target of
therapeutic management of such neurological complications.
Some reports, though fragmentary, do emphasize about the roles of
SIRT3 in neuroprotection against certain neurodegenerative conditions
and thus, advocate about multimodal research on SIRT3 biochemistry
in the relevant animal models of neurodegenerative brain disorders.
The current research so far has ably recorded identification of meta-
bolic protein targets for SIRT3 and its regulation in maintaining mi-
tochondrial metabolism and ROS balance at cellular level. As such these
reprots invite and open at least 3 fundamental aspects of SIRT3 biology
in the context of brain biochemistry:
1. Regulation of nuclear transcription of SIRT3 and characterization of
the factors accountable for its targeting to mitochondria in normal
and diseased brain cells
2. The report on the role of SIRT1 in regulating some of the disease
50
Journal of Chemical Neuroanatomy 95 (2019) 43–53
associated signaling steps during AD, PD & Hutington’s disease
(Herskovits and Guarente, 2013) do argue for a crucial role of SIRT3
as well and thus, inviting special scientific focus to delineate SIRT3
signaling associated with neurodegeneration.
3. The cause and effect relationship of SIRT3 vs excitotoxic and neu-
rodegenerative brain disorders is still in its infancy stage. This needs
to be given due focus, because this is likely to provide end point
evaluation parameters about modulation of SIRT3 activity by small
molecule and also for understanding the reverse pharmacology of
plants derived neuroprotectants.
Declaration
The authors declare no conflict of interest.
Acknowledgments
This review originated due to research work on SIRT1 financed by
an ICMR project (P-54/38/GFPGER/2011/NCD-II and currently the
research on SIRT3 is being financially supported by a DST project (ER/
2016/006501/AS). The award of UGC merit fellowship to Anamika and
Lady Tata memorial Trust JRF/SRF to Archita Khanna are also ac-
knowledged. The facilities of DST-FIST & UGCeCAS programme in the
Department of Zoology and from DBT-BHU ISLS have been of great
support.
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