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Mitochondrion 7 (2007) 359–366
G. Cannino, C.M. Di Liegro, A.M. Rinaldi *
Dipartimento di Biologia Cellulare e dello Sviluppo ‘‘A.Monroy'', University of Palermo, Italy
Received 3 April 2007; received in revised form 24 July 2007; accepted 24 July 2007
Available online 2 August 2007
The biogenesis of mitochondria depends on the coordinated expression of nuclear and mitochondrial genomes. Consequently, the
control of mitochondrial biogenesis and function depends on extremely complex processes requiring a variety of well orchestrated reg-ulatory mechanisms. It is clear that the interplay of transcription factors and coactivators contributes to the expression of both nuclearand mitochondrial respiratory genes. In addition, the regulation of mitochondria biogenesis depends on proteins that, interacting withmessenger RNAs for mitochondrial proteins, inﬂuence their metabolism and expression. Moreover, a tight regulation of the import andﬁnal assembly of mitochondrial protein is essential to endow mitochondria with functional complexes. These studies represent the basisfor understanding the mechanisms involved in the nucleus–mitochondrion communication, a cross-talk essential for the cell.
Ó 2007 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
Keywords: Mitochondria; Transcriptional factors; Post-transcriptional regulation; RNA-binding proteins
alterations (). Mitochondrial prolif-
Eukaryotic cells contain a large number of mitochon-
eration occurs in response to electrical stimulation of mus-
dria, which are essential for cell metabolism. In fact, these
cle, following training exercise (and during
organelles perform pyruvate dehydrogenation, Kreb's
thermogenesis adaptation in rodent brown fat
cycle, and oxidative phosphorylation, the energy-generat-
Proliferation of defective mitochondria
ing processes coupling the oxidation of substrates to the
takes place in certain mitochondrial myopathies, in which
synthesis of nearly all cellular ATP. In addition, mitochon-
aﬀected muscles are characterized by the presence of rag-
dria are involved in the synthesis of amino acids, nucleo-
ged red ﬁbres ). Presumably, this pro-
liferation is a nuclear response to mitochondrial DNA
proliferation, motility and programmed death
(mtDNA) mutations leading to deﬁciencies in ATP produc-
tion, but the mechanisms underlying these events are
Mitochondria malfunctioning is related to aging
poorly understood at the molecular level. Mitochondrial
and to the onset of many diseases, including cancer
proliferation and massive ampliﬁcation of mtDNA take
place during oogenesis in sea urchin. The resulting mito-
). The number, structure, and func-
chondrial genomes are distributed to the embryo cells until
tions of mitochondria diﬀer in animal cells and tissues in
very late developmental stages, when embryonic mtDNA
relation to the energetic needs
replication resumes (
and they can vary during development and diﬀeren-
Interestingly, mitochondrial mass in Para-
tiation, or in response to physiological or environmental
centrotus lividus embryos is constant during development,while respiratory activity is enhanced at fertilization and
increases from 16 blastomeres until gastrula
Corresponding author. Tel.: +39 0916577441; fax: +39 0916577430.
E-mail address: (A.M. Rinaldi).
Experiments on enucleated sea urchin eggs
1567-7249/$ - see front matter Ó 2007 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
G. Cannino et al. / Mitochondrion 7 (2007) 359–366
demonstrated that a negative control is exerted by the
2. Transcriptional regulation
nucleus over mitochondrial mtDNA activity: mitochon-drial DNA does not replicate, and it is not transcribed,
The identiﬁcation of transcription factors regulating the
as long as the nucleus is present (
expression of nuclear genes encoding mitochondrial respi-
Mitochondrial genome consists of a double-
ratory components represents a good experimental tool
stranded covalently closed circular DNA molecule of about
for elucidating the mechanisms involved in the intergenom-
16.5 kb in vertebrates. Many mtDNA molecules are pack-
ic cross-talk (). In general, it is
aged within mitochondria into small clusters called nucle-
thought that several regulatory circuits might exist in
oids (), or chondriolites, that vary in
response to diﬀerent physiological stimuli, or that diﬀerent
size and number in response to physiological conditions
regulatory pathways are activated for the expression of dif-
ferent groups of genes. In other words, several factors reg-
Nucleoid structure is stabilized by TFAM,
ulating the transcription of many nuclear genes for
or mtTFA, which binds to mtDNA and regulates its abun-
mitochondrial proteins were isolated, but so far no com-
dance (The maintenance of the integrity
mon feature has been identiﬁed for the regulation of all
of mitochondrial DNA is important for keeping proper cel-
involved genes in a coordinated manner
lular functions both under physiological and pathological
The promoters of many genes
conditions ). Mitochondria contains
coding for OXPHOS proteins and other mitochondrial
about 1500 diﬀerent proteins, only half of which have been
enzymes were characterized. It was demonstrated that they
identiﬁed ). Metazoan mtDNA encodes
do not exhibit canonical TATA and CAAT boxes, have
13 mRNAs for subunits of the oxidative phosphorylation
heterogeneous initiation sites, and contain complex and
complexes (OXPHOS) (
promoter-speciﬁc regulatory regions that can diﬀer even
). Proteins of mitochon-
among genes encoding subunits of the same complex (
drial origin are translated on mitochondrial ribosomes
The expression of many proteins of
bound to the matrix side of the inner membrane, and co-
the OXPHOS complexes, like cytochrome c oxidase, the
translationally inserted into the proper compartment (
terminal component of mitochondrial respiratory chain,
is regulated at transcriptional level through speciﬁc
mRNAs for mitochondrial proteins are transcribed in the
nucleus () and translated by cytoplasmic ribo-
). NRF1 (nuclear respiratory factor 1), the ﬁrst iso-
somes. Proteins are eventually imported into mitochondria
lated mammalian factor common to the expression of
) and distributed to diﬀerent com-
nuclear respiratory genes, functions as a positive regulator
partments (inner and outer membrane, matrix and inter-
of transcription (
membrane space) ). These
The target genes of NRFs (NRF-1 and NRF-2)
two pathways must converge at some point for those mul-
encode subunits of the OXPHOS complexes or proteins
timeric complexes assembling nuclear and mitochondrial
involved in the expression, assembly, and function of the
gene products. It is noteworthy that the machineries for
complexes ). In mammals, it has been dem-
both pathways are composed entirely by nuclear-coded
onstrated that NRF-1 is able to bind the promoters of
proteins. Recently, by genomic and proteomic approaches,
genes encoding components of mtDNA transcription
experiments were devoted to identify new pathways for the
machinery (TFAM, TFB1M, TFB2M, and POLRMT)
biogenesis of the inner and outer membranes, for the
(whose mechanisms of action are being
assembly and export of proteins from matrix to the inner
membrane and for the addition of new components to
over, NRF-1 seems to be related to the expression of mito-
the existing pathways ().
chondrial and cytosolic enzymes of the heme biosynthetic
One group of nuclear genes contributes with catalytic
pathway, and to components of the protein import and
and auxiliary proteins to the mitochondrial enzymatic
assembly machinery, suggesting that it plays a role in
activity. A second group includes all the factors that regu-
late the expression of nuclear and mitochondrial OXPHOS
NRF-2 regulates the transcription of mtTFA in human,
genes ), while a third group encodes factors
mouse, and rat (and mtTFA
responsible for the import, assembly, and ﬁnal localization
is responsible for the transcription of the mitochondrial-
of mitochondrial polypeptides (
encoded COX subunits I, II, and III, that are transcribed
). Thus, nuclear genome has a leading role in the bio-
synthesis of the respiratory chain (
Ongwijitwat and Wong-Riley demonstrated
nevertheless, although rela-
that, in neurons, NRF-2 is able to regulate all the
tively few, mitochondrion-encoded proteins participate in
nuclear-encoded COX subunits at the transcriptional level.
the formation of mitochondrial oxidative phosphorylation
Thus, NRF-2 may play a critical role in regulating the syn-
thesis of the cytochrome c oxidase subunits in response to
Moreover, nuclear activity can be modulated by signals
changes in neuronal energy demand
sent by mitochondria ().
Human cytochrome c1 promoter seems
G. Cannino et al. / Mitochondrion 7 (2007) 359–366
to be modulated by two transcription factors, E2F1 and
urchin embryos, we found evidence that at least one com-
E2F6, but they do not exert the same eﬀects on other addi-
plex of 40 kDa can be formed by a region of the 30-UTR
tional promoters of OXPHOS genes, suggesting that the
of the hsp56 messenger RNA and a binding protein which
members of the E2F family are not general modulators
is more abundant in the outer mitochondrial membrane
of OXPHOS gene expression ).
The activity of transcription factors is increased by coreg-
ulators, which usually exist as multiprotein complexes in
the nucleus. This class of proteins can be highly regulated
and represents the primary targets of hormonal control
other hand, they were described factors involved in post-
and signal transduction pathways
transcriptional regulation of mitochondrial RNAs, such
). The PGC-1 (peroxisome proliferator-activated
as the RBP38 protein, probably implicated in RNA stabil-
receptor (PPAR) coactivator 1) family plays a critical role
ization (). In Saccharomyces cerevisiae,
in the control of tissue-speciﬁc biological processes and in
it was demonstrated that the translation and assembly of
the regulation of mitochondrial oxidative metabolism
the subunits II and III of COX complex depends upon
(The PGC-1 coactivators are highly versa-
nucleus-encoded translation activators, which speciﬁcally
tile, interacting with diﬀerent transcription factors that
recognize the 50-untranslated leader of the mRNAs
directly regulate the expression of certain nuclear genes
). We demonstrated
for mitochondrial products
that, in developing rat brain, the amounts of COXIII pro-
these include NRF-1
tein and mRNA are not linearly related, suggesting that
and NRF-2, whose genes are themselves targets of PGC-
COXIII expression could also be regulated at post-tran-
1a (PGC-1a and b stimulate the biogene-
scriptional levels ). Recently, we
sis of mitochondria with diﬀerent metabolic characteristics,
described two diﬀerent factors able to bind COXIII
thus, by modulating the relative activity of these two coac-
mRNA, present in the mitochondrial extracts of adult rat
tivators, cells may achieve ﬁne-tuning of mitochondrial
brain and testis, respectively. These tissue-speciﬁc factors
function in response to speciﬁc metabolic needs
could participate in COXIII mRNA translation and/or
localization in mitochondrial inner membrane
Taken together, these data suggest that transcriptional
). Mitochondrial extracts from rat brain also
factors and nuclear coactivators orchestrate the programs
contain a factor able to bind COXIV mRNA 30-UTR,
of expression of both genomes, essential to cellular energet-
whose binding ability decreases during brain diﬀerentia-
ics, therefore they can be considered main players of the
tion. The same mRNA is bound by proteins present in
communication between nucleus and mitochondria.
post-mitochondrial extracts from heart, kidney, and testis.
These results suggest the existence of diﬀerent tissue-spe-
3. Post-transcriptional regulation
ciﬁc post-transcriptional regulatory factors, or the occur-rence of post-translational modiﬁcations of the same
Increasing evidences demonstrate the importance of
mRNA localization, stability, and translation regulation
During liver development
in the control of gene expression, in both developmental
), in brown adipose
and diﬀerentiated cells; such regulation mostly relies upon
tissue ) and in kidney cells (
the activity of RNA-binding proteins (
the regulation of the expression of the b-sub-
unit of the mitochondrial H+-ATP synthase is also exerted
lar activity of RNA-binding proteins is regulated by their
at the level of mRNA translation. The translation of b-
abundance, by the availability of speciﬁc regulatory mole-
mRNA mostly depends on the 30UTR of the mRNA that,
cules and/or by post-translational modiﬁcation of their
interacting with the translational machinery
) and resembling internal ribosome entry sites
Mili and colleagues described human
LRP130 protein, component of the PPR (pentatricopeptide
behaves as a positive regulator. In fetal liver and in hepato-
repeat motif) group of RNA-binding proteins, which is
mas, Cuezva and colleagues found proteins that, binding to
localized both in the nucleus, where it is associated with
the 30UTR of the mRNA (30 FBPs), interfere with the
post-splicing mRNP complexes, and in mitochondria,
translation-enhancing activity of the 30UTR of the mRNA
where it binds polyadenylated mRNAs. This suggests that
LRP130 could participate in coordinating the expression of
hence regulating mitochondrial biogenesis in hepatocytes
nuclear and mitochondrial genomes (
It was also found that mouse AKAP121 (kinase A
anchoring protein) expressed in HeLa cells carries MnSOD
Since many data exist concerning the activity of RNA-
mRNA in proximity of mitochondrial outer membrane,
binding proteins in both multicellular and unicellular
promoting its translation, thus facilitating the import into
systems, it is possible to hypothesize that, despite the bio-
mitochondria Interestingly, in sea
logical diﬀerences between models, the regulation involving
G. Cannino et al. / Mitochondrion 7 (2007) 359–366
protein–mRNA interactions might represent a general
membranes, insertion of essential cofactors, assembly and
mechanism of the regulation of nuclear–mitochondrial
ﬁnal maturation of the enzyme
A novel gene product of the dihydrolipoamide suc-
Reversible protein acetylation is emerging as a critical
cinyltransferase gene, MIRTD (mitochondrial respiration
post-translational modiﬁcation involved in the regulation
generator of truncated DLST), mediates the molecular
of many biological processes. Although most of the pio-
assembly of the cytochrome c oxidase complex (COX), so
neering experiments focused on the role of histone acetyla-
that MIRTD mRNA decrease could aﬀect energy produc-
tion in transcriptional control, recent ﬁndings have
tion. The level of MIRTD mRNA is signiﬁcantly low in the
generalized the concept to many non-histone proteins
brains of AD (Alzheimer's disease) patients, also conﬁrm-
Interestingly, it was demon-
ing the idea that COX defect can cause the disease (
strated that mammalian mitochondria contain intrinsic
NAD-dependent deacetylase activity. This deacetylase is
In conclusion, diﬀerent post-transcriptional and post-
the nuclear-encoded SirT3, homologous to yeast Sir2 (
translational mechanisms operate in the regulation of mito-
and it is located within mitochondrial
chondrial biogenesis and activity. Future investigation
matrix. SirT3 activity could lead to the constitutive deacet-
eﬀorts should be devoted to the understanding of the rela-
ylation of one or several mitochondrial proteins
tionships between the components of these regulation
). SirT3 activates mitochondrial functions and
plays an important role in adaptive thermogenesis, stimu-lating CREB phosphorylation, which directly activates
4. Mitochondria to nucleus communication
PGC-1a promoter ). Recently, it was foundthat, under normal cell growth conditions, SirT3 localizes
Nuclear gene expression can be inﬂuenced by signals
not only to mitochondria, but also to the nucleus, and it
coming from mitochondria, a process called retrograde
is transported from the nucleus to mitochondria upon cell
stress ). SirT1, another mammalian
homolog of yeast Sir2, was shown to modulate PGC-1a,
so that the regulation of mitochondrial activity
leading to enhanced transcriptional activity in an NAD+-
depends on a bidirectional ﬂow of information. In yeast,
dependent way ) and, in addition,
the retrograde signaling pathway functions as a homeo-
inducing a metabolic gene transcription program of
static or stress response mechanism, to adapt various
mitochondrial fatty acid oxidation
biosynthetic activities to the alterations of metabolic
Mitochondrial activity is regulated also by modulating
Sekito and collabora-
the import and assembly of proteins and, during the last
tors suggested a model for the control of signaling from
years, several novel components of these pathways have
mitochondria to nucleus, in which the cells with dysfunc-
been identiﬁed. TIM23 complex and the presequence trans-
tional mitochondria send one or more signals to nucleus
locase-associated motor, the PAM complex, mediate the
via Rtg2p: the dephosphorylation of a highly phosphor-
multistep import of pre-proteins with cleavable N-terminal
ylated form of Rtg3p leads to its transient dissociation
signal sequences into the matrix or inner membrane of
from Rtg1p and to the translocation of Rtg1p and Rtg3p
mitochondria ), while the inner
to the nucleus. Here they bind the GTCAC box sites of
membrane contains several components that mediate the
target genes and consequently activate transcription
sorting and assembly of these proteins. Together, the trans-
In skeletal mammalian myoblasts and in
location and assembly complexes coordinate mitochondria
human pulmonary carcinoma cells, mitochondrial retro-
biogenesis Moreover, increasing evidences
grade signaling seems to occur through cytosolic [Ca2+]i
indicate that chaperones participate not only in protein
folding, but also in assembling and maintaining mitochon-
The alteration of mitochondrial membrane potential
drial complexes ). A recently
(DW) reduces mitochondrial Ca2+ uptake and, in turn,
discovered sorting and assembly machinery (SAM com-
it reduces ATP availability, causing reduction of calcium
plex) is essential for integration and assembly of outer-
eﬄux into storage organelles or outside the cells.
membrane proteins (). For example,
Increased cytosolic Ca2+ concentration in turn activates
the pathway of VDAC (voltage-dependent anion-selective
calcineurin, and related factors such as Ca2+-dependent
channel) biogenesis in human mitochondria involves the
kinases, causing the activation of diﬀerent nuclear tran-
TOM complex, Sam50, and metaxins. The deletion of
scription factors (Interest-
Sam50, the central component of SAM, led to a defect in
ingly, the absence of mitochondrial function blocks
the assembly of VDAC (
myotube diﬀerentiation, probably through the speciﬁc
Cytochrome c oxidase (COX) biogenesis includes a variety
of steps from translation to the formation of the mature
(). The retrograde signaling could
complex. Each step involves a set of speciﬁc factors that
be realized by the translocation of some mitochondrial
assist translation of subunits, their translocation across
proteins to the cytoplasm, and/or into the nucleus.
G. Cannino et al. / Mitochondrion 7 (2007) 359–366
According to such hypothesis, we recently found that, in
6. Concluding remarks
developing rat brain, cytochrome c oxidase subunit III islocalized not only in mitochondria, but is also present in
Mitochondrial function must rely on an orchestrated
the cytosol (), where it could exert a
cross-talk between nuclear and mitochondrial genes and,
although the genomes are physically distinct, they should
Even if these data were obtained in diﬀerent systems and
be considered interdependent from the functional point
the molecular mechanisms so far described are diﬀerent,
of view. In this review, we discuss the communication
one can look at retrograde communication as a common
between nucleus and mitochondria and the mechanisms
necessary mechanism modulating nuclear–mitochondrial
that could regulate this complex interplay. From the
above-mentioned works, it appears clear that nucleus hasa dominant role in the regulation of mitochondrial activity.
5. Mitochondria and cancer
Nuclear-coded transcriptional factors control the activityof mitochondrial genome, coordinating the expression of
Genetic and/or epigenetic alterations of mitochondrial
both nuclear and mitochondrial genes for mitochondrial
functions cause a large variety of degenerative diseases,
proteins. In addition, nucleus activity makes use of pro-
aging, and cancer
teins that regulate translation, stability, and localization
An expanding number of autosomal diseases
of the mRNAs, both of nuclear and mitochondrial origin,
were associated with mitochondrial DNA depletion and
modulating developmental and/or tissue-speciﬁc expres-
multiple deletions. These disorders are due to defects of
sion. RBPs' activity could represent a mechanism involved
intergenomic communication, in fact mutations of nuclear
in the nucleus to mitochondrion communication. Other
genes for mitochondrial proteins possibly disrupt the nor-
nucleus-encoded proteins participate in the control of the
mal cross-talk that regulates the number of mtDNA copies
import of mitochondrial proteins and ensure the correct
and expression of mitochondrial genes, as suggested by
assembly of OXPHOS complexes. The coordination
between transcriptional and post-transcriptional regulation
An association between mitochondrial dysfunction and
mechanisms might be due to ‘‘compensation'' factors,
cancer was made by and metabolic
responsible for the regulation of respiratory enzymes syn-
aberrations associated with mitochondrial bioenergetic
thesis, according to the requirements of subunits assembly
functions in cancer cells were observed
in fully functioning complexes. Nonetheless, nuclear gene
The relationship between mitochondrial
expression can be inﬂuenced by signals coming from mito-
disorders and mutations was documented for several doz-
chondria, through retrograde communication, so that the
ens of nuclear genes encoding proteins directly or indi-
regulation of mitochondrial activity requires a bidirectional
rectly involved in the biogenesis of the respiratory chain
ﬂow of information.
complexes Most human car-cinomas express reduced amounts of the catalytic subunit
of H+-ATP synthase (In con-trast, the expression of nuclear encoded cytochrome c
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Efficacy and safety of a fixed-dose combinationof dutasteride and tamsulosin treatment(Duodart™) compared with watchful waiting withinitiation of tamsulosin therapy if symptoms donot improve, both provided with lifestyle advice,in the management of treatment-naïve men withmoderately symptomatic benign prostatichyperplasia: 2-year CONDUCT study resultsClaus G. Roehrborn, Igor Oyarzabal Perez*, Erik P.M. Roos†, Nicolae Calomfirescu‡,Betsy Brotherton§, Fang Wang¶, Juan Manuel Palacios**, Averyan Vasylyev†† andMichael J. Manyak§
Impregnated central venous catheters for prevention of bloodstream infection in children (the CATCH trial): a randomised controlled trial Ruth E Gilbert, Quen Mok, Kerry Dwan, Katie Harron, Tracy Moitt, Mike Millar, Padmanabhan Ramnarayan, Shane M Tibby, Dyfrig Hughes, Carrol Gamble, for the CATCH trial investigators* SummaryBackground Impregnated central venous catheters are recommended for adults to reduce bloodstream infections but Published Onlinenot for children because there is not enough evidence to prove they are eﬀ ective. We aimed to assess the eﬀ ectiveness March 3, 2016of any type of impregnation (antibiotic or heparin) compared with standard central venous catheters to prevent http://dx.doi.org/10.1016/