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The coordination of nuclear and mitochondrial genomes plays a pivotal role in maintenance of mitochondrial biogenesis and functionality during stress and aging. Environmental and cellular inputs signal to nucleus and/or mitochondria to trigger interorganellar compensatory responses. Loss of this tightly orchestrated coordination results in loss of cellular homeostasis and underlies various pathologies and age-related diseases. Several signaling cascades that govern interorganellar communication have been revealed up to now, and have been classified as part of the anterograde (nucleus to mitochondria) or retrograde (mitochondrial to nucleus) response. Many of these molecular pathways rely on the dual distribution of nuclear or mitochondrial components under basal or stress conditions. These dually localized components usually engage in specific tasks in their primary organelle of function, whilst upon cellular stimuli, they appear in the other organelle where they engage in the same or a different task, triggering a compensatory stress response. In this review, we focus on protein factors distributed between the nucleus and mitochondria and activated to exert their functions upon basal or stress conditions. We further discuss implications of bi-organellar targeting in the context of aging.
Nucleus and mitochondria are the two main genome-bearing organelles of the eukaryotic cell with central and orchestrating roles in cellular and organismal physiology. Mitochondria lay at the core of cellular metabolism with critical involvement in many enzymatic and signaling pathways affecting energy production, cell proliferation, differentiation and survival. Besides the fact that mitochondria contain their own genome, mitochondrial DNA (mtDNA) encodes only for ∼1% of the total mitochondrial proteome. The rest 99% is encoded by nuclear genes, translated in the cytoplasm and then translocated in the sub-mitochondrial compartment to which they are destined. A significant proportion of mitochondrial proteins are translated by ribosomes that reside on the outer mitochondrial membrane and are imported co-translationally (
Mitonuclear communication is governed by key factors and signaling cascades that have been identified in different species and are classified as anterograde or retrograde signaling. Anterograde signaling includes the most traditional perspective of the nucleus as regulatory factor coordinating the function of subcellular organelles. The nucleus integrates cellular and environmental signals to adjust its function and the function of other organelles. Usually, this involves the function of transcription factors regulating gene expression. Several transcription factors have been shown to regulate distinct classes of mitochondrial genes. In mammalian cells, these are nuclear respiratory factor 1 (NRF1), activating genes involved in respiration, heme biosynthesis, mitochondrial DNA replication and transcription (
Reversely, mitochondria can sense stress signals and convey them to the nucleus to initiate adaptive responses. This type of signaling from a peripheral organelle to the nucleus is known as retrograde response. Mitochondrial retrograde response is amongst the most well studied retrograde signaling pathways. It was firstly described in
Apart from these complex signaling cascades that mediate the communication of nucleus to mitochondrial and vice versa a more direct way of interorganellar coordination has emerged, which relies on the redistribution of nuclear or mitochondrial proteins between the two compartments. Nuclear proteins with mitochondrial distribution are mainly transcription factors that translocate to mitochondria upon a stress stimulus or reside in mitochondria under steady state conditions and are activated upon stress. Mitochondrial proteins with nuclear distribution are transcription factors with roles both in mitochondrial and nuclear DNA, biosynthetic enzymes or pro-apoptotic factors. To a great extent, this dual localization of proteins can be achieved through the presence of two (or more) targeting signals within the amino acid sequence which are revealed under specific conditions. It is conceivable that this level of interorganellar communication and coordination is very important as it allows for direct and finely tuned responses of both organelles leading to enhanced, precise and acute stress adaptation. In this review we will focus on nuclear and mitochondrial proteins with dual distribution between nucleus and mitochondria and their roles in the heterologous compartment. Finally, we will discuss the reported implications of this bi-organellar coordination in the process of aging.
In the following section we will focus on predominantly nuclear proteins, mainly transcription factors, found to reside in mitochondria, either under steady state conditions or upon cellular or environmental signals (
Nuclear proteins with defined roles in mitochondria.
Protein | Species | Mitochondrial function | Stimulus driving mitochondrial localization | Reference |
---|---|---|---|---|
NF-κB | Rat, mouse | Suppression of mitochondrial genes | Steady-state conditions | |
CREB | Rat, mouse | Activation of mitochondrial genes | Steady-state conditions | |
MEF-2D | Mouse | Transcriptional Activation of ND6 | Steady-state conditions | |
TERT | Human, mouse, Rat | Reverse Transcription of mitochondrial tRNAs, |
Oxidative stress, steady state conditions | |
RECQL4 | Human, mouse | Restores mtDNA replication, Ensures mtDNA integrity | Steady-state conditions | |
STAT3 | Mouse, human | Modulation ETC through direct binding to respiratory complexes | Steady-state conditions |
|
P53 | Rat, mouse, human | Modulation of mitochondrial permeability, apoptosis and necrosis, |
Pro-apoptotic signals, oxidative stress, hypoxia, ultraviolet irradiation | |
IRF3 | Human | Apoptosis induction by mitochondrial recruitment of BAX | RNA virus infection | |
STAT1 | Mouse, Rat | ND | Steady-state conditions | |
HIF-1α | Human | ND | Hypoxia |
NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a dimeric transcription factor. The NF-κB family consists of five members; p65 (RelA), p105/p50 (NF-κB1), p100/p52 (NF-κB2), c-Rel and RelB. Normally NF-κB resides in the cytoplasm in complex with its inhibitor IκB (Inhibitor of κB). Upon stimulation, IkB is being phosphorylated and subsequently degraded, unmasking the nuclear targeting signal of NF-κB which is now free to translocate to the nucleus. Stimulation comes by various stress signals like inflammatory cytokines, low oxygen tension, bacterial lipopolysaccharide (LPS), elevated cytoplasmic calcium levels or DNA damage (
The cAMP response element-binding protein (CREB) is a ubiquitous transcription factor that regulates cellular growth, proliferation and differentiation with critical roles in neuronal plasticity and long term memory formation in the brain, as well as with specific functions in immune responses (
Myocyte Enhancer Factor-2D (MEF2D) belongs to the Myocyte enhancer factor 2 (MEF2) family of transcription factors with important roles in muscle differentiation, immune cell responses, glucose metabolism (in adipocytes), cellular development and survival (in neurons;
Telomerase is a ribonucleoprotein with multiple functions. Primarily, it is responsible for telomere elongation (
Telomerase reverse transcriptase affects mitochondrial function in distinct ways. Transcriptome analysis of proliferative and quiescent tissues from fourth generation
Apart from the nuclear function of TERT affecting mitochondrial function, TERT is known to physically target the organelle. In higher eukaryotes (human, mouse, and rat) TERT contains a bipartite nuclear targeting signal, that regulates its shuttling in and out of the nucleus, and amitochondrial targeting sequence (MTS), that guides a fraction of endogenous TERT to the mitochondrial matrix. Mitochondrial TERT is imported in a membrane potential-dependent manner and it is localized in close proximity with the inner membrane (
RecQL4 (RecQ Like Helicase 4) belongs to the human family of RECQ DNA helicases and its role in DNA metabolism has been well-documented. Upon laser-induced DNA double strand breaks (DSBs), nuclear RECQL4 is accumulated at the DNA break sites. RECQL4 deficient cells failed to repair DNA DSBs and were sensitive upon exposure to γ-irradiation, suggesting a role of RECQL4 in DNA repair process (
The signal transducer and activator of transcription (STAT) family of proteins are transcription factors involved in a variety of cellular functions including apoptosis, immune responses, tumorigenesis, cell proliferation and autophagy. The family consists of seven members (STAT1, 2, 3, 4, 5A, 5B, and 6). STATs conduct signals from a variety of cytokines through their corresponding receptors with the participation of Janus kinases, JAK1-3 and TYK2. These kinases phosphorylate STATs following cytokine signals leading to their homodimerization and translocation to the nucleus where they exert their function by either activating or repressing nuclear genes. STAT3 has a well-documented role in the nucleus. The canonical pathway of STAT3 activation includes phosphorylation on tyrosine 705 by JAK1, JAK2, and TYK2. These kinases are activated by cytokine signaling (IL1, IL6, LIF, and OSM among others). Tyrosine 705 phosphorylation of STAT3 promotes formation of STAT3 homodimers which enter the nucleus stimulating induction of STAT3-responsive genes. These are involved in development, chronic inflammation, acute phase response, tumorigenesis, DNA damage and metabolism (
P53 protein is often referred to as “the guardian of the genome” due to its roles in DNA damage repair. As a transcription factor, alongside its DNA repair role, nuclear p53 can regulate diverse cellular functions such as apoptosis, cell cycle, metabolism and autophagy. Several autophagy-related genes have been found among the p53 transcriptional targets. These genes can be specifically induced upon DNA damage both in mouse and human cells and act toward tumor suppression and apoptosis induction in an-undefined manner (
Apart from its role in cell death mitochondrial p53 has been assigned several other functions mainly within the mitochondrial matrix. Indicatively, upon oxidative stress, mitochondrial translocated p53 interacts with manganese superoxide dismutase (MnSOD) reducing its scavenging capacity (
RNA virus infection activates the latent transcription factor IRF-3 (Interferon Regulated Factor 3) causing its nuclear translocation and the induction of many antiviral genes. Upon virus infection, a transcriptionally inactive mutant of IRF3 targets mitochondria and promotes apoptosis by directly interacting with pro-apoptotic BAX. The IRF3/BAX interaction, which is mediated by the BH3-like domain of IRF3, recruites BAX onto mitochondria upon viral-RNA infection (
Phosphorylated STAT1 has a well-documented tumor suppressor function in mammalian cells (
HIF-1 (hypoxia-inducible factor 1) is a dimeric transcription factor that consists of an O2-regulated subunit, Hif-1α, and a constitutively expressed subunit, Hif-1β. HIF-1 is a key regulator of metabolic adaptations based on oxygen availability, conserved in all metazoans species. HIF-1α is constitutively degraded in normoxia in a proteasome-dependent manner. Upon hypoxia HIF-1α is stabilized in the cytoplasm and targets the nucleus where it induces a transcriptional program which confers adaptation to hypoxia. It has been reported that upon hypoxia endogenous HIF-1α targets mitochondria, along with the nucleus in a cell line of human colon carcinoma (
Several mitochondrial proteins exhibit nuclear localization upon cellular and environmental stimuli. These include transcription factors, enzymes, and pro-apoptotic factors. Their nuclear contribution is mediated by transcriptional or non-transcriptional events (
Mitochondrial proteins with defined roles in the nucleus.
Protein | Species | Nuclear function | Stimulus driving nuclear localization | Reference |
---|---|---|---|---|
TFAM | Mouse, Rat, Human | Transcription of nuclear genes |
Steady-state conditions | |
ATFS-1 | Transcription of genes associated with OXPHOS, glycolysis, mitochondrial chaperons and proteases (UPRmt) | Mitochondrial dysfunction |
||
CLK-1/COG-7 | Promotes the expression of genes associated with oxidative stress response | Mitochondrial dysfunction |
||
Fumarase/FH | Yeast, Human | Production of fumaric acid at the site of DSBs |
Ionizing radiation, Hydroxyurea | |
PDC | Human | Production of nuclear CoA for histone acetylation | Mitochondrial dysfunction |
|
Nfs1 | Yeast | ND | Steady-state conditions | |
MNRR1 | Human | Transcription of COX4I2 and its own |
Oxidative or hypoxic stress | |
AIF | Yeast Human | Induces DNA fragmentation and chromatin condensation |
Ionizing radiation |
|
HIGD1A | Human | ND | Hypoxic stress and DNA damage |
The mitochondrial transcription factor A (TFAM) is a nuclear encoded protein with mandatory mitochondrial targeting, essential for both transcription and replication of mitochondrial DNA (
In
Clock 1 (CLK-1) and its human homolog Coenzyme Q7 Homolog (COQ7), is a mitochondrial enzyme involved in the biosynthesis of ubiquinone which in turn is required for proper ETC function (
Mitochondrial nuclear retrograde regulator 1 (MNRR1) is a regulator of cytochrome c oxidase (COX) activity through direct interaction. Under physiological conditions, MNRR1 is transported into mitochondria, where it is predominantly located, through the mitochondrial intermembrane space import and assembly 40 (MIA40) system (
Apoptosis inducing factor (AIF) is a mitochondrial flavoprotein with pro-apoptotic functions conserved from yeast to mammals. The mitochondrial role of AIF is controversial. It could participate in cellular bioenergetics through its NADH oxidase activity as has been shown
The enzyme fumarase (FH) is conserved among species and represents a well-known paradigm for dual targeted proteins (
Cytosolic FH can move to the nucleus in response to DNA damage. In an attempt to understand the exact role of FH in both compartments, a yeast strain lacking nuclear FH gene was generated with a copy of FH inserted into its mitochondrial genome. Thus, FH was absent from the cytosol and exclusively present in mitochondria where it preserved TCA function. It has been shown that yeast cells lacking of cytosolic FH exhibit increased sensitivity to DNA damage induced by IR)and hydroxyurea (HU). Exposure to IR and HU cause DSBs and inhibition of DNA synthesis, respectively. When cytosolic FH is present and mitochondrial enzymatic activity is disturbed, yeast cells are again sensitive to DNA damage, suggesting that both cytosolic and mitochondrial activity of FH is required for resistance to DNA damage. However, nuclear FH does not act as a DNA repair protein (
Pyruvate dehydrogenase complex (PDC) is an essential mitochondrial protein complex consisting of three enzymes, the pyruvate dehydrogenase-E1, dihydrolipoamide transacetylase-E2, and dihydrolipoamide dehydrogenase-E3 (
In
Hypoxia-inducible gene domain 1A (HIGDA1) is a mito chondrial protein interacting with complex IV in yeast, and with complex III in humans (
Mitochondria are metabolic hubs regulating cellular energy homeostasis, ROS production and stress adaptation, among others. All these key cellular pathways have been causatively liked to the aging process. It is, therefore, widely accepted that mitochondria have decisive roles in aging. Given their pronounced contribution to aging, it is conceivable that mechanisms regulating their ability to adapt to cellular and environmental stimuli, may all have critical implications to the aging process. In the following section we will focus on the reported roles of differentially distributed nuclear or mitochondrial proteins in the context of aging.
Nuclear transcription factors that translocate to mitochondria are master regulators of cellular homeostasis with numerous reports on their role on organismal aging. However, their mitochondrial functions have not been directly linked to aging up to now. Nevertheless, several links to aging related diseases and cellular senescence have been made. Examples are described below.
cAMP response element-binding protein’s role in neuronal plasticity and cognitive function is highly studied. It is known that its activity is reduced in the aged brain and upon neurodegeneration (
Myocyte enhancer factor-2D’s role in neuroprotection is well-documented. Although a direct link with aging has not been established yet, mitochondrial MEF2D is implicated in Parkinsons Disease (PD). Mice treated with neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a precursor molecule of MPP+, exhibit typical pathology of PD (
It has been proposed that accelerated mutation rate in nuclear or mtDNA could be causatively linked to the aging process. A mutant mouse strain expressing an error-prone polymerase gamma (POLG1) accumulates random mutations in its mitochondrial genome and exhibits progeria-like characteristics (
Telomere maintenance has a well-documented role in the aging process (
Mitochondrial dysfunction has been correlated with a variety of pathologies, many of which are age-related. Paradoxically, studies in invertebrates revealed a beneficial effect of mild mitochondrial dysfunction in aging and age-related disease models. Evolutionary conservation of this paradox exists in mammals (
Both
ATFS-1 was shown to translocate to nucleus upon mitochondrial oxidative or proteotoxic stress (
The causative association of UPRmt to lifespan extension has recently been challenged. Gain-of-function
Many nuclear and mitochondrial proteins with bi-organellar distribution have been identified so far, however, our understanding of their roles in the heterologous compartment is limited. Identification of additional players participating in this type of direct bi-organellar communication will be the challenge of future studies. Intriguing implications of mitonuclear coordination with the aging process as well as with age-related diseases are expected to emerge. These advances will expand our understanding and our ability to design and implement new strategies toward holistic treatments promoting quality of life in old age.
EL and IG wrote the manuscript. NT reviewed and edited the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Work in the authors’ laboratory is funded by grants from the European Research Council (ERC), the European Commission Framework Programmes, and the Greek Ministry of Education. IG is supported by the European Union Seventh Framework programme through the Marie Curie Initial Training fellowship (Ageing Network - MarriAge).