The Mitochondrion as a Primary Site

of Action of Regulatory Agents Involved

in Neuroimmunomodulation
A.M.G. PSARRA,a S. SOLAKIDI,b AND C.E. SEKERISb
a Foundation for Biomedical Research of the Academy of Athens, Center for
Basic Research, 11527 Athens, Greece
b NationalHellenic Research Foundation, Institute of Biological Research and
Biotechnology, Laboratory of Molecular Endocrinology, 11635 Athens, Greece

ABSTRACT: A major system of neuroimmunomodulation is the

hypothalamic-pituitary-adrenocortical (HPA) axis, acting through glu-
cocorticoids and their intracellular signaling components, exerting both
stimulatory and inhibitory effects on the immune reaction. Glucocorti-
coids inhibit the production of proinflammatory cytokines by interact-
ing with nuclear transcription factors (nuclear factor [NF]-B, activated
protein [AP]-1) and induce the production of several anti-inflammatory
cytokines by gene activation. In some cells and/or in extreme stress
conditions, apoptosis is evoked. In most processes related to neuroim-
munomodulation a prominent role is emerging for mitochondria. These
organelles generate more than 90% of the cells energy requirements
through oxidative phosphorylation (OXPHOS), which is regulated by
several agents, including steroid and thyroid hormones. These hormones
are inducers of nuclear and mitochondrial OXPHOS gene transcription
and they exert a primary action not only on nuclear but also on mito-
chondrial genes by way of cognate receptors. Recently, additional nuclear
transcription factors involved in neuroimmunomodulation have been de-
tected in mitochondria (NF-B, AP-1, p53, calcium/cAMP response el-
ement binding protein [CREB]), and binding sites of these and putative
binding sites of other nuclear transcription factors have been identified
in the mitochondrial genome. The interaction of these factors with mito-
chondrial regulatory proteins, with receptors and with the genome has
been shown and, in some cases, modulation of mitochondrial transcrip-
tion was observed with possible effects on energy yield. The mitochon-
dria store a host of critical apoptotic activators and inhibitors in their
intermembrane space and the release of these factors could be another
possible mode of action of the mitochondrially translocated regulatory
agents and receptors.

Address for correspondence: Prof. CE Sekeris, 48 Vas Constantinou Ave, 11635 Athens, Greece.
Voice: 0030-210-7273767; fax: 0030-210-7273677.
e-mail: csekeris@eie.gr

Ann. N.Y. Acad. Sci. 1088: 1222 (2006). 

C 2006 New York Academy of Sciences.

doi: 10.1196/annals.1366.019

12
PSARRA et al.: MITOCHONDRIA AND NEUROIMMUNOMODULATION 13

KEYWORDS: neuroimmunomodulation; mitochondrion; transcription

factors; steroid/thyroid receptors; oxidative phosphorylation; apoptosis

INTRODUCTION
The modulation of the immune response by neuronal and hormonal agents is
currently receiving strong experimental support. In this context, the autonomic
nervous system, the hypothalamic-pituitary-adrenocortical (HPA) axis, and
the sympathetic-neural-adrenomedullary systems exert both stimulatory and
inhibitory effects on the immune reaction, through hormones, other regulatory
agents, and their intracellular signaling components.1,2
Glucocorticoids represent major regulatory agents of the immune and in-
flammatory response, inhibiting the production of proinflammatory cytokines
and chemokines (such as tumor necrosis factor (TNF)-, interleukin (IL)-2,
IL-6, IL-1, IL-8, and RANTES [regulated on activation normal T cell
expressed and secreted]), as well as cytokine receptors, whereas they in-
duce the synthesis of anti-inflammatory cytokines (such as IL-10, IL-4, and
TGF-) by activating transcription of respective genes.3,4 The inhibitory ef-
fects of glucocorticoids on the proinflammatory elements are exerted by
crosstalk with nuclear transcription factors and signaling pathways, such as
nuclear factor (NF)-B and activated protein (AP)-1. Glucocorticoids thus
lead to negative effects on the transcription of immunoregulatory genes, con-
taining the respective NF-B and AP-1 binding sites on their promoters or
regulatory regions.5 Glucocorticoids also regulate thymocyte and lymphocyte
selection and survival and some of their functions.6
In addition to the important nuclear events, recent findings point to the
emerging role of mitochondria in neuroimmunomodulation. Mitochondria rep-
resent the principal energy source of the cell, providing more than 90% of its
needs by way of oxidative phosphorylation (OXPHOS). Furthermore, mito-
chondria contain the enzymes needed for free fatty acid metabolism, the Krebs
cycle, and the key steps of heme biosynthesis and hormone synthesis. Addi-
tionally, the mitochondria generate the majority of cellular reactive oxygen
species (ROS), have specialized scavenging systems to protect themselves and
the cell from these toxic byproducts, and host key machinery for programmed
cell death, serving, therefore, as gatekeepers of apoptosis.7 The energy require-
ments of the cell fluctuate depending on the physiological state, are higher in
metabolically demanding developmental conditions and lower when the cell
initiates a series of steps leading to apoptosis, the attenuation of energy pro-
duction being one of the early events in this process.
Steroid and thyroid hormones are major regulators of energy yield, by exert-
ing rapid, nongenomic effects, as well as by inducing nuclear and mitochondrial
OXPHOS genes.8 These hormones exert their actions not only at the nuclear,
but also at the mitochondrial level, by way of cognate receptors localized both
in cell nucleus and mitochondria.8
14 ANNALS NEW YORK ACADEMY OF SCIENCES

In addition to hormone receptors, other nuclear transcription factors known

to play a major role in neuroimmunomodulation, such as NF-B, AP-1, p53,
and calcium/cAMP response element binding protein (CREB), have been
detected in mitochondria. The role of these nuclear transcription factors on
mitochondrial physiology and their potential crosstalk with nuclear emanat-
ing processes in neuroimmunomodulation is now beginning to receive due
consideration.

STEROID AND THYROID HORMONE RECEPTORS

IN MITOCHONDRIA

In the past decade, steroid and thyroid hormone receptors have been de-
tected in mitochondria of animal cells. Glucocorticoid receptors were first
detected in rat liver mitochondria by the Western blotting of mitochondrial
extracts, using specific antibodies to the receptor and by immunogold electron
microscopy.9 Subsequently, glucocorticoid receptors were found in mitochon-
dria from various sources, such as HeLa cells,10 rat brain cells,11 C 2 C 4 mouse
glial cells,12 salamander retina Mueller cells,13 and recently in human hepato-
carcinoma HepG2 and osteosarcoma SaOS-2 cell lines.14 Estrogen receptors
have also been detected in mitochondria of various cells.1520 Recently, an-
drogen receptors were also found in mitochondria of human spermatozoa and
human prostate cancer LnCap cells.20 The mitochondria-specific thyroid hor-
mone receptor p46, a truncated form of TR-, was also detected21 and its
importance in transcription regulation was demonstrated.8 Thyroid hormone
receptor was also demonstrated in HeLa cells by immunofluorescence confo-
cal microscopy.8,22 Other members of the nuclear receptor family present in
mitochondria are the retinoic acid receptor (RAR),23,24 the retinoic X receptor
(RXR), and the orphan receptor Nur70.25

OTHER NUCLEAR TRANSCRIPTION FACTORS

PRESENT IN MITOCHONDRIA

NF-B

The presence of NF-B in mitochondria was reported in 2001.26 An interac-

tion of the inhibitory protein IB- with the mitochondrial ATP/ATP translo-
cator ANT1, using a two-hybrid system in yeast was shown. This led to the
detection of an IB-/p65-NF-B complex in mitochondria and the demon-
stration of the p65 molecule in mitochondria of Jurkat cells, by immunogold
electron microscopy. The p65 molecule was found in the intermembrane space
and was shown to be released together with IB- after induction of apoptosis
in Jurkat cells, upon engagement of the Fas surface molecule with the spe-
cific CH11 antibody. In a subsequent report,27 a mitochondrial localization of
PSARRA et al.: MITOCHONDRIA AND NEUROIMMUNOMODULATION 15

NF-B and IB- was also demonstrated in U937 cells, by immunogold elec-
tron microscopy and immunoprecipitation in rat liver mitochondria by respec-
tive antibodies. Cytokine treatment of the cells led to reduction of expression
of the mitochondrially encoded cytochrome oxidase III and cytochrome b mR-
NAs, whereas inhibition of the activation prevented the loss of expression of
COXIII and cyt b mRNAs, pointing to a negative role of NF-B on mitochon-
drial mRNA expression. Recently, NF-B (p65 and p50) with DNA-binding
activity was detected in mitochondria of human prostate cell lines.28 By elec-
trophoresis mobility shift analysis (EMSA) it was also shown that treatment of
the cells with the TNF-related apoptosis-inducing ligand (TRAIL) increased
DNA binding of NF-B without changing the amount of p65 in mitochondria,
suggesting activation of NF-B without additional translocation of NF-B sub-
units to mitochondria. TRAIL treatment also led to decreased mitochondrial-
genome-encoded mRNA levels, which was prevented by inhibition of NF-B,
suggesting a role of NF-B in the mitochondrial genome transcription pro-
cess.28
Overexpressed ANT1 in HeLa cells led to a recruitment of the IB-/NF-
B complex into mitochondria with a coincidental decrease in nuclear NF-
B DNA-binding activity and downregulation of the antiapoptotic genes Bcl-
X L , MnSoD 2, and cIP 2 .29 It was proposed that mitochondrial recruitment of
NF-B following ANT1 overexpression was correlated to the proapoptotic
activity of ANT1.

AP-1

The presence of AP-1 in mitochondria was demonstrated in studies investi-

gating the effects of glutamic acid and its agonist kainate on brain function.30
The excitatory amino acid L-glutamate participates in various neuronal pro-
cesses, ranging from transient signal communication to long-term plasticity
and immunomodulation. This is accomplished through the interaction of glu-
tamic acid with ionotropic and metabotropic receptors in the central nervous
system (CNS), the former classified into NMDA, alpha-amino-3-hydroxy-
5-methyisoxazole-4-propionate, and kainate receptors. Glutamic acid signals
lead to increased expression of both the c-fos gene and the c-Fos protein in mice
and potentiation of DNA-binding activity of AP-1. In particular, the glutamic
acid agonist kainate, known to induce the expression of c-Fos, c-Jun, JunB,
and JunD, was administered to mice and 13 h later an enhanced AP-1 binding
to DNA was detected in both mitochondrial and nuclear extracts of cerebral
cortex and hippocampus. c-Fos was detected within mitochondria of subfield
CA pyramidal and dental granular cells in hippocampus, by immunogold elec-
tron microscopy. DNA binding was inhibited by oligonucleotides containing
sequences similar to the AP-1 binding site detected in the noncoding region of
mitochondrial DNA. It was suggested that kainate may facilitate the expression
of the AP-1 complex and its subsequent translocation into mitochondria, where
16 ANNALS NEW YORK ACADEMY OF SCIENCES

it could participate in mechanisms associated with transcriptional regulation

of mitochondrial DNA.30 In a follow-up article, the potential binding sites
of AP-1, corresponding to its nuclear binding sites, were identified in the
noncoding region of the mitochondrial DNA (sequences MT1 to MT10).31
Enhanced binding of AP-1 to sequences MT-3 and MT-9 was demonstrated
by electrophoretic mobility shift analysis with mitochondrial extracts from
hippocampi 26 h after kainate administration. In a recent article reporting
the presence of NF-B in prostate carcinoma cell mitochondria,26 mitochon-
drial DNA-binding activity to AP-1 binding sequences was detected and it was
significantly increased after TRAIL treatment of these cells.26

CREB

In studies concerning the possible importance of CREB in synaptic trans-

mission, retrograde memory and brain function, this transcription factor was
detected in mitochondria of rat brain and particularly in the inner mitochon-
drial membrane, by immunoblotting and immunogold electron microscopy.32
It was also shown that mitochondrial CREB can be phosphorylated by protein
kinase A and, as demonstrated by EMSA, can bind to double-stranded DNA
containing the calcium-cycle AMP-responsive element consensus sequence. In
a recent article that confirmed the previous findings, it was demonstrated that
CREB is located in the matrix of the inner mitochondrial membrane of rat brain
cells and that a calcium-dependent phosphatase regulates its phosphorylation
state.33

p53

p53 was detected in membranes of mitochondria of fibroblasts of primary

cultures of human skin and in cytoplasmic organelles, presumably mitochon-
dria, of PHA-stimulated peripheral blood mononuclear cells.34 Other research
groups working with human HT1080 and murine C3H10T1/2 cells demon-
strated, by immunoprecipitation using p53 and GRP75 (heat shock protein)
antibodies, the presence of a p53-heat shock protein complex in mitochondrial
extracts.35 They also demonstrated the presence of p53 in mitochondria by im-
munogold electron microscopy. At the onset of p53-dependent apoptosis, after
either DNA damage or hypoxia, a small, but significant, p53 fraction of stress-
induced p53 was detected in the inner membrane fraction but also within the mi-
tochondria of human cell lines, which was not the case during p53-independent
apoptosis or during p53-mediated cell arrest.36 The translocation of p53 into
mitochondria was rapid, preceding the release of cytochrome c and procaspase
activation, and was blocked by overexpression of the antiapoptotic protein
Bcl-2. Targeting of p53 to mitochondria, using a mitochondrial import leader
sequence, was sufficient to induce apoptosis in p53-deficient cells. Later, it
PSARRA et al.: MITOCHONDRIA AND NEUROIMMUNOMODULATION 17

was shown that the wild-type p53 protein directly induces mitochondrial per-
meabilization and cytochrome c release by forming inhibitory complexes with
protective BclXL and Bcl2 proteins.37 Some authors did not find a p53 con-
sensus DNA-binding site by mitochondrial genome computer search.36 Others,
however, identified a putative p53 binding sequence in mitochondrial DNA,
implying a direct effect of p53 on mitochondrial transcription/replication.38 A
role of p53 in mitochondrial transcription and translation processes in stress-
related conditions has been proposed.3943 In cell lines conditionally immor-
talized with SV40, the proliferative potential is temperature-dependent. At the
restrictive temperature, heat inactivation of the large T antigen caused p53
release, growth arrest, and apoptosis. A lower mitochondrial membrane po-
tential (m) was observed, which correlated with an uncoupling of electron
transport from ATP production. This was linked to the induction of apoptosis
and associated with a decrease in the rate of mitochondrial translation.39
During early-stage response of HA-1 fibroblasts to oxidative stress, when
extensive growth arrest and moderate apoptosis was observed, degradation of
mitochondrial, but not nuclear, DNA took place,40 accompanied by downreg-
ulation of mitochondrial, but not nuclear, RNA, encoding OXPHOS. Yoshida
et al.41 observed, corroborating previous findings, that at the onset of p53-
dependent apoptosis, a fraction of p53 localized in mitochondria and could
interact with the mitochondrial transcription factor mtTFA, enhancing its ca-
pacity to bind to cis-platin-damaged DNA, which indicated the involvement
of p53 in the mitochondrial transcription process. A direct role of p53 in
mitochondrial transcription has been suggested.42 Treatment of NIH3T3 cells
with a dominant negative p53 mutant led to decreased mitochondrial 16s rRNA
and decreased staining of the mitochondria with the mitochondria-specific dye
Mitotracker Red CMXRos. Altered expression of mitochondrial 16s rRNA has
also been shown by differential RNA display in p53 knockout mouse embryos
at the neurulation stage.38

NUCLEAR TRANSCRIPTION FACTORS IN MITOCHONDRIA:

MODULATORS OF MITOCHONDRIAL TRANSCRIPTION
AND APOPTOSIS

The detection of numerous transcription factors in mitochondria that are

involved in immunomodulation, metabolic growth, developmental processes,
and apoptosis, raises the question of the role of these factors in mitochondrial
physiology and mitochondrial-linked processes. Practically all steroid and thy-
roid hormones affect some of these processes, not only by way of cognate
receptors, which modulate gene activity, but also by initiating rapid hormonal
effects through signal transduction pathways. The same nuclear receptors, in
some cases in a variant form, have also been detected in mitochondria. The
other nuclear transcription factors localized in mitochondria, are activators or
18 ANNALS NEW YORK ACADEMY OF SCIENCES

inhibitors of transcription of several nuclear genes, either by direct interaction

with the nuclear genome or indirectly by interaction with other DNA-binding
proteins, such as the nuclear receptors. Many of the affected genes are involved
in immunomodulation, including genes encoding cytokines, chemokines, and
cytokine receptors.
The role within the confines of mitochondrion of nuclear transcription fac-
tors translocating into the organelle, particularly after the action of agents
involved in immunomodulation and stress induction, is therefore in the cen-
ter of interest. Regarding the nuclear receptor superfamily, experimental evi-
dence has accumulated supporting an action in transcription within the con-
fines of the mitochondrion, in a similar way as within the confines of the
nucleus.8,43
Effects on mitochondrial RNA metabolismtranscription, processing,
turnover, and translationhave been experimentally supported, regarding the
action of NF-B and p53 found in mitochondria.27,42 Consensus sequences
for these and other nuclear transcription factors have been determined in a
computer search of the mitochondrial genome.44 In this context, the interac-
tion of steroid hormone receptors with NF-B and AP-1, which is observed in
the extramitochondrial space and plays a major role in modulating gene tran-
scription, could also take place within the mitochondria.5,45 The mitochondrial
genome is totally devoted to energy production, as it solely encodes compo-
nents of the OXPHOS complexes and RNA translation machinery. All cell-
regulatory actions, including those involved in neuroimmunomodulation, are
energy-dependent and are coupled to mitochondria. Depending on the degree
of energy requirement, the mitochondria can respond to lower energy needs
by allosteric activation of the OXPHOS chain and, in case of high demands,
by increased expression of the OXPHOS enzymes. Steroid and thyroid hor-
mones are known to exert their effects on energy metabolism by both genomic
and nongenomic mechanisms.8 Transcription factors localized in mitochon-
dria could, therefore, also exert such a dual action. DOK-4 is a member of
the downstream kinase family of adaptor proteins, an anchoring molecule for
the tyrosine kinase c-src (also found in mitochondria), which enhances the
production of TNF--mediated ROS, TNF--mediated NF-B activation, and
effects on complex I of the respiratory chain.46 The presence of DOK-4 in
mitochondria of endothelia points to the participation of src-kinase in mito-
chondrially mediated inflammatory responses and to mitochondrial NF-B
action on immunomodulation by rapid nongenomic effects.
Concerning apoptosis and the role of mitochondria and the mitochondrial
transcription factors in this process it seems that these organelles store in
their intermembrane space a panel of critical apoptotic activators and effec-
tors of cell death, including cytochrome c, Smart/diabolo, AIF, and procaspase
2, and 9. A growing list of proapoptotic proteins that translocate to mito-
chondria and exert their proapoptotic functions interacting with the apop-
totic agents stored in the organelles has been observed. Some of the effects
PSARRA et al.: MITOCHONDRIA AND NEUROIMMUNOMODULATION 19

of the translocating transcription factors on apoptosis could be exerted through

nongenomic mechanisms, as described for the action of NF-B27 and p53.47
The factors determining the choice between transcription-dependent and
-independent mechanisms are still poorly understood.

EPILOGUE

Mitochondria are the main energy providers of the cell by way of OXPHOS,
but also perform a series of other important functions. Their role in develop-
ment, particularly in connection with muscle differentiation and pathophysiol-
ogy of neuromuscular diseases, in aging and apoptosis is now being recognized.
In addition to proteins involved in these processes, several translocating pro-
teins not previously associated with mitochondrial functions and belonging to
other biochemical classes are now being detected in mitochondria. Emerging
categories of such proteins are the nuclear hormone receptors and the tran-
scription factors NF-B, AP-1, CREB, and p53. These proteins serve known
developmental, growth, metabolic and neuroimmunomodulatory functions by
way of genomic and nongenomic molecular mechanisms of action. Their pres-
ence in mitochondria, after translocation from the cytoplasm under diverse
conditions, such as neuroimmunomodulation, suggests that these molecules
in the mitochondria are involved in similar regulatory events as exerted in the
nucleus, thus complementing and amplifying them. The experimental results
supporting this concept are still mainly fragmentary and of a descriptive nature.
However, the growing interest in this emerging field and the increasing rate
of relevant research papers heralds rapid progress in our in-depth understand-
ing of the role of mitochondria and the mitochondrially translocated nuclear
transcription factors in neuroimmunomodulation.

ACKNOWLEDGMENTS

We thank the Bodossaki Foundation for financial support.

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