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The complex crosstalk between mitochondria and the nucleus: What goes in between?夽
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Umut Cagina , José Antonio Enriqueza,b,∗ a b
Departamento de Desarrollo y Reparación Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias Universidad de Zaragoza, Zaragoza, Spain
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Article history: Received 12 December 2014 Received in revised form 21 January 2015 Accepted 29 January 2015 Available online xxx
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Keywords: Mitochondria Oxidative phosphorylation Mitochondrial capacity Mitochondrial diseases Retrograde signaling
Mitochondria are critical metabolic hubs in which catabolic and anabolic cellular processes converge and are integrated. To perform their function, mitochondria also need to respond to signals that monitor their function and send continuous feedback to the nucleus and other organelles to trigger the required expression programs (for example, stabilization of hypoxia-inducible factor 1 − ˛). Unsurprisingly, mitochondrial dysfunction results in wide range of disorders. Understanding how cells adapt to changes in mitochondrial function is critical for the evaluation of mitochondrial disorders and the development of potential treatments. Each type of mitochondrial dysfunction results in a unique transcriptional response. Here we review the role of nuclear-encoded factors in the response to changes in mitochondrial function and discuss their relevance to metabolic homeostasis, outlining the diverse and complex ways in which nuclei adapt to maintain mitochondrial homeostasis. This article is part of a Directed Issue entitled: Mitochondrial Diseases. © 2015 Published by Elsevier Ltd.
1. Introduction Organelle facts: - Mitochondrial dysfunction activates regulatory pathways that induce changes in nuclear gene expression able to monitor the organelle status. - Mitochondrial function is connected to cell signaling pathways through changes in redox and phosphate pairs (NAD/NADH; CoQH2/CoQ and ATP/ADP vs. AMP), critical metabolite concentrations (succinate, aK-glutarate, AcetylCoA, etc.), and reactive oxygen species (ROS) production. - Variations in mitochondrial status modulate specific transcriptional programs. - The process that transduces the information required for the cell to adapt to a mitochondrial challenge is called “retrograde signaling”.
夽 This article is part of a Directed Issue entitled: Mitochondrial Diseases. Q2 ∗ Corresponding author at: Centro Nacional de Investigaciones Cardiovasculares Carlos III, Departamento de Desarrollo y Reparación Cardiovascular, Melchor Fernandez Almabro 3, 28029 Madrid, Spain. Tel.: +34 914531200; fax: +34 914531240. E-mail address: [email protected] (J.A. Enriquez).
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Mitochondria are well known for their role of producing energy by oxidative phosphorylation, but these organelles also make critical contributions to other areas of cell metabolism, information flux (calcium, ROS, etc.) and cell-death cascades (apoptosis). The first clinical report of a genuine mitochondrial dysfunction was published by Rolf Luft in 1959 (Ernster et al., 1959). Since then, a number of diseases have been linked to mitochondrial dysfunction, and current figures show that 1 in every 5000 individuals are affected by a mitochondrial disorder (Pfeffer et al., 2012). The wide range of pathologies caused by mitochondrial dysfunction include lactic acidosis, skeletal myopathy, deafness, neurodegenerative diseases, muscular disorders, cardiomyopathy, diabetes and cancer (Vafai and Mootha, 2012). The varied symptoms and the involvement of multiple tissues make mitochondrial disorders hard to diagnose and treat, and diagnosis is best achieved by identifying the underlying genetic alteration. Mitochondrial dysfunction can alter cell signaling because of its primary role in synthesizing critical metabolites (NADH/NAD+ , ATP/ADP, ATP/AMP, succinate/a-ketoglutarate, etc.). Mitochondrial dysfunction can thus affect sirtuin-mediated signaling (NADH/NAD+ ), AMPK signaling (ATP/AMP), mTOR signaling (ATP/ADP) or Hif1a signaling (succinate/a-ketoglutarate), and can
http://dx.doi.org/10.1016/j.biocel.2015.01.026 1357-2725/© 2015 Published by Elsevier Ltd.
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also impact signaling mediated by reactive oxygen species (ROS) or Ca2+ (Jones et al., 2012). Depending on the cell type and type of mitochondrial dysfunction, one or several of these paths might be especially affected. Understanding the detailed signaling response to mitochondrial dysfunctions will help to generate a better understanding of the complex puzzle of mitochondrial disorders. 2. Organelle function
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In addition to these signaling molecules, which monitor cell metabolic status and thus mitochondrial performance, information about mitochondrial quality is also transduced to the cell via specific mitochondria-derived pathways, among which the mitochondrial unfolding protein response (mtUPR) is gaining much attention (Mottis et al., 2014). It has also been suggested that mitochondria-to-nucleus retrograde signaling can be envisioned as a complementary mechanism to these mitochondrial quality control systems (Jazwinski, 2013). Changes in nuclear gene expression to maintain mitochondrial homeostasis are not limited to nuclear-encoded mitochondrial proteins. The retrograde response also changes the global nuclear gene expression pattern. Identifying the components of these changes was the first question to be addressed by research into mitochondria-nuclear interactions in the late 1980s. Communication between the mitochondrial and nuclear genomes was first postulated in 1987 in yeast (Parikh et al., 1987). The first factors implicated in retrograde signaling (including COX VI, CIT2 and RTG proteins) were also identified in yeast (Butow et al., 1988; Jia et al., 1997; Liao et al., 1991; Liu and Butow, 2006; Rothermel et al., 1997) (Table 1). Further analysis of Rtg proteins (Rtg1–3) showed that these proteins are normally present in the cytoplasm and translocate to nucleus upon retrograde signaling (Sekito et al., 2000). Subsequent studies in yeast also characterized more factors and also signaling pathways such as RAS2 and the TOR signaling pathway (Butow and Avadhani, 2004; Kirchman et al., 1999; Liu and Butow, 2006) (Table 1). The TOR pathway has also being linked to Rtg proteins in the context of retrograde signaling (Breitkreutz et al., 2010; Dilova et al., 2004; Dilova et al., 2002; Giannattasio et al., 2005; Komeili et al., 2000). Furthermore, yeast studies have shown that dysfunctional mitochondria inhibit TORC1 (Kawai et al., 2011). These studies were followed by others that examined retrograde signaling in more depth and also in other cell types and organisms. Understanding the conservation of the retrograde response between species is very important and therefore studies different organisms are important, especially regarding the differences in mitochondrial homeostasis between yeast and animal cells, particularly during mitochondrial biogenesis (Heddi et al., 1993; Jazwinski, 2013; Poyton and McEwen, 1996). In mammalian cells, the first proteins implicated in retrograde signaling (Cox-Va, b-actin, myc, GAPDH, EF-1) were characterized after the studies carried out in yeast (Marusich et al., 1997; Wang and Morais, 1997) (Table 1). Several studies subsequently revealed the diverse nature of mammalian retrograde signaling, including activation of NFAT, ATF2, NFKb, MAPK, PKC, Egr-1 and CEBP, and CamKIV-mediated activation of CREB (Amuthan et al., 2002; Arnould et al., 2002; Biswas et al., 1999, 2003; Butow and Avadhani, 2004). It should be noted that NFKb has roles in mitochondrial biogenesis and the response to ROS (Srinivasan et al., 2010).
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2.1. Conservation and diversity in retrograde signaling
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Several microarray analyses in yeast showed that mitochondriato-nucleus communication is not limited to a handful of factors
but is instead a global response alters the expression levels of different sets of genes depending on the type of mitochondrial dysfunction (Epstein et al., 2001; McCammon et al., 2003; Traven et al., 2001). Consistent with the yeast studies, the mTOR pathway has been implicated in retrograde signaling in mammalian cells, confirming the conserved nature of retrograde signaling between species (Komeili et al., 2000; Laplante and Sabatini, 2012). Although the retrograde signaling response has yet to be resolved in full, nuclear response elements commonly involved in mitochondrial dysfunction along with more specific ones have been identified. Genome-wide microarray transcriptome studies have been especially important in identifying genes that are differentially expressed upon mitochondrial dysfunction. These studies had performed using different cell lines; one of the earliest studies used a mtDNA depleted human breast cancer cell line (Delsite et al., 2002). However, there is no consensus in the published data. The type of mitochondrial dysfunction seems to have a strong influence on the observed pattern of nuclear gene expression. This has been shown by comparing the expression profiles of Rho0 (mtDNA-depleted) cells and cells carrying the A3243G mutation, which suggests partially distinct multiple pathways of retrograde signaling (Jahangir Tafrechi et al., 2005). Furthermore, RT-PCR and GeneChip microarray analyses consistently show non-identical gene expression patterns in different Rho0 cells lines (Miceli and Jazwinski, 2005; Mineri et al., 2009). 2.2. Key players in the transcriptional response Nonetheless, some signaling pathways are repeatedly reported to be involved in retrograde signaling: mTOR, NFKB, c-JUN/JNK and RXRA, NFATs, PKC, CamK IV, PI3K/AKT, Sirt1, No/CO (Jones et al., 2012). The importance of these pathways is further supported by the implication of defined transcription factors such as MYC, CREB, CEBP, FOXO-1, Egr-1, NRF-1, TFAM, ATF2, ctBP1, and PGC-1a/PRC (Jones et al., 2012).
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Cells affected by mitochondrial dysfunction have to adapt to the sub-optimal energy metabolism. The most common adaptive response to decreased mitochondrial ATP production is increased glycolytic flux to lactate (von Kleist-Retzow et al., 2007). In yeast, the metabolic adaptation to an incomplete TCA cycle requires production of metabolites such as glutamate (Butow and Avadhani, 2004). Therefore cell survival in these circumstances can be helped by the use of alternative and more varied carbon sources. Common mechanisms observed in yeast are increased glyoxylate cycle activity and fatty acid -oxidation (Jazwinski, 2013), mechanisms also triggered by nutrient deprivation (Wang et al., 2010). In addition, microarray studies of mtDNA-depleted cells revealed that TCA cycle and glyoxylate cycle genes are controlled similarly (Epstein et al., 2001). These metabolic changes in the switch from OXPHOS to glycolysis were corroborated by transcriptomic analysis in Drosophila melanogaster OXPHOS mutants (Freije et al., 2012). However, cells cannot depend solely on glyoxylate cycle for survival, and must therefore activate additional mechanisms. 3.2. Mitochondrial biogenesis, capacity and clearance The purpose of nuclear–mitochondrial cross-talk is to achieve a fine-tuned and functional mitochondrial population. The cell should have the required amount of healthy mitochondria and clear any unhealthy organelles. Mitochondrial quality control is the term usually used to describe the set of events and processes geared
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Table 1 Historical outline of retrograde signaling in yeast and mammals.
Yeast
Mammalian
Significance
Genes & pathways identified
References
Discovery of first factors
RTGs, CIT1, CIT2, COX VI
First signaling pathways
RAS2, TOR
Parikh et al. (1987), Butow et al. (1988), Liao et al. (1991), Rothermel et al. (1997), Sekito et al. (2000) Kirchman et al. (1999), Komeili et al. (2000), Dilova et al. (2002), Butow and Avadhani (2004) Epstein et al. (2001), Traven et al. (2001), McCammon et al. (2003) Marusich et al. (1997), Wang and Morais (1997)
First transciptome studies Discovery of first factors First signaling pathways
-Actin, EF-1, myc, Cox-Va, SD Calcium signaling, CREB signaling, NFK
First transciptome studies
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to achieving optimum mitochondrial homeostasis. The four main events in this process are biogenesis, mitophagy, fusion/fission and movement (MacAskill and Kittler, 2010; Scarpulla, 2011; Youle and Narendra, 2011; Chan, 2012). Mitochondrial biogenesis and fission have been shown to determine the capacity of cells to adapt to respiratory chain dysfunction, and nitric oxide has also been shown to be important for retrograde signaling (Benard et al., 2013). In addition, a major role in the clearance of accumulated proteins from mitochondria is played by the mtUPR (Martinus et al., 1996). The mtUPR is activated in Caenorhabditis elegans upon OXPHOS dysfunction (Haynes and Ron, 2010). Several transcription factors participate in mtUPR activation, including CHOP and CEBP, overlapping TFs associated with retrograde signaling (Horibe and Hoogenraad, 2007). Adjustments to mitochondrial biogenesis and capacity are also triggered by other kinds of cellular stress and upon changes in the metabolic environment. Mitochondrial biogenesis is regulated by nuclear-encoded proteins, transcription factors and co-activators (Scarpulla, 2006, 2011), but also maintains a degree of autonomy (Enriquez et al., 1999). The transcription factors NRF1, NRF2, ERR␣, CREB, and YY1 can regulate the expression of nDNA and, indirectly, mtDNA encoded mitochondrial genes, resulting in adjustments to mitochondrial function and oxidative capacity (Basu et al., 1997; Scarpulla, 2011; Schreiber et al., 2004; Vercauteren et al., 2006). In addition to TFs, an even more important role in mitochondrial biogenesis is played by transcriptional co-activators. The ‘master regulator’ of mitochondrial biogenesis is the widely studied transcriptional co-activator PGC1␣ (Lin et al., 2005; Scarpulla, 2012; Wenz, 2011). The known downstream TF targets of PGC1␣ are PPARs (regulators of fatty acid oxidation), NRF1 and ERR␣ (regulators of mitochondrial biogenesis) (Wenz, 2013). PGC1␣ has two homologues, PGC1B and PRC (PGC1 related co-activator), which have partially overlapping functions (Gleyzer and Scarpulla, 2011, 2013; Scarpulla, 2011). The three PGC factors are induced or activated in response to a variety of cellular stresses. PGC1␣ expression is regulated by other factors, including YY1, mTOR, CREB, PPARs, and p53 (Cunningham et al., 2007; Sahin et al., 2011; Scarpulla, 2008a,b). PGC1␣ activity can also be adjusted by post-translational modification by Akt, p38 MAPK, AMPK and Sirt1 (Canto and Auwerx, 2009; Fan et al., 2004). The three main metabolic changes that regulate PGC1␣ are caloric restriction, ROS and hypoxia (reviewed in detail in Wenz, 2013), with all three cases affecting mitochondrial performance. Regulation of mtDNA gene expression requires proteins encoded by nDNA. Nuclear-encoded TFs needed for mitochondrial transcription are POLRMT, TFB2M, TFAM and MTERFs (Arnold et al., 2012; Peralta et al., 2012). Mitochondrial transcripts are translated in the specific mitoribosomes (see Rorbach and Minczuk, 2012). Mammalian mtDNA encodes for only 13 proteins, all of which are subunits of OXPHOS complexes. All other OXPHOS protein subunit are encoded by nDNA. The co-assembly of OXPHOS subunits into
Biswas et al. (1999, 2003), Amuthan et al. (2001, 2002), Arnould et al. (2002) Delsite et al. (2002), Jahangir Tafrechi et al. (2005), Miceli and Jazwinski (2005)
complexes and supercomplexes is therefore a very intricate process that requires the action of dedicated chaperones (Ghezzi and Zeviani, 2012; Lapuente-Brun et al., 2013; McKenzie et al., 2011; Q4 Mick et al., 2010) (Fig. 1). 4. Organelle pathology The link between mitochondrial dysfunction and disease has led to intense research into the role of mito-nuclear signaling to develop potential treatments (Cerutti et al., 2014; Khan et al., 2014; Pirinen et al., 2014). A recent comparative analysis of tranciptomic data from different species (human, fly, mouse and worm) showed that mitochondrial dysfunction involves the dysregulation of conserved genes involved in the retrograde signaling response (Zhang et al., 2014). Two major human health problems that appear to be tightly linked to alterations in the mito-nuclear signaling are aging-related diseases and cancer (Reeve et al., 2008; Swerdlow, 2009). 4.1. Aging Lifespan studies in C. elegans suggest that mitochondrial-nuclear crosstalk is an important determiner of lifespan, with lifespan extended by increased glyoxylate cycle activity and knock-down of certain respiratory genes (Cristina et al., 2009; Lee et al., 2010; Vanfleteren and De Vreese, 1995). ROS, HIF1-␣ and mtUPR are implicated in these processes and also in the development of neurodegenerative disorders (Durieux et al., 2011; Houtkooper et al., 2013; Lee et al., 2010; Rugarli and Langer, 2012). Lifespan extension phenotypes have also been observed in D. melanogaster with respiratory chain dysfunction (Copeland et al., 2009; Liu et al., 2011), and the role of the mtUPR response has also been demonstrated in mice (Houtkooper et al., 2013). Loss of mitochondrial homeostasis is also linked to neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease (Lin et al., 2002; Simon et al., 2004). 4.2. Cancer A link between mitochondria and cancer has been proposed repeatedly. However, the contribution of mitochondrial dysfunction to invasiveness and transformation remains unresolved (Amuthan et al., 2001, 2002; Guha et al., 2007). Some studies suggest that the metastatic phenotype is affected by mtDNA mutations that lead to depletion of mtDNA as a consequence of increased ROS signaling (Ishikawa et al., 2008; Kulawiec et al., 2009). Retrograde signaling involving both well functioning and dysfunctional mitochondria, has been implicated in cancer. More recent work showed that a metastatic phenotype can result from overloading of the electron transport chain due to excess superoxide production (Porporato et al., 2014). Furthermore, PGC1␣ may also contribute to cancer progression (Jones et al., 2012). In some tumors linked
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Fig. 1. Overview of retrograde signaling. There are at least four types of mitochondrial dysfunction, which lead to the generation of at least five types of signal: ATP/AMP, NADH/NAD+ , ROS, cytosolic Ca2+ , reduction in membrane potential ( ). Activation of signaling (red arrows) triggers changes in nuclear gene expression that promote diverse responses represented by purple arrows
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to mtDNA mutations and associated mitochondrial defects, mitochondrial biogenesis is upregulated in an apparently compensatory mechanism (Gasparre et al., 2011)). 5. Future outlook A comprehensive knowledge of the interconnected roles of mitochondrial quality control and mito-nuclear signaling will provide the key to a better understanding of human health disorders in which mitochondrial dysfunction plays role, from mitochondrial diseases to metabolic syndrome and degenerative diseases. This knowledge can be expected to pave the way to new treatments to achieve better quality of life for people affected by these conditions. Uncited references Laplante, 2012. Acknowledgements
We thank Dr. Concepción Jimenez for technical assistance. 278 Q6 This study was supported by grants from the Ministerio de 279 Economía y Competitividad (SAF2012-1207 & CSD2007-00020), 280 the Comunidad de Madrid (CAM/API1009), the EU (Mitochondrial 281 European Educational Training, MEET: European Commission Sev282 enth Framework Programme, FP7-PEOPLE-2012-ITN MARIE CURIE, 283 grant agreement No. 317433) and the Instituto de Salud Carlos III 284 (FIS grant PI11-00078). The CNIC is supported by the Ministerio de 285 Q7 Economía y Competitividad and the Pro-CNIC Foundation. 277
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Organelles in focus
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The complex crosstalk between mitochondria and the nucleus: What goes in between?夽
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Umut Cagina , José Antonio Enriqueza,b,∗ a b
Departamento de Desarrollo y Reparación Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias Universidad de Zaragoza, Zaragoza, Spain
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Article history: Received 12 December 2014 Received in revised form 21 January 2015 Accepted 29 January 2015 Available online xxx
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Keywords: Mitochondria Oxidative phosphorylation Mitochondrial capacity Mitochondrial diseases Retrograde signaling
Mitochondria are critical metabolic hubs in which catabolic and anabolic cellular processes converge and are integrated. To perform their function, mitochondria also need to respond to signals that monitor their function and send continuous feedback to the nucleus and other organelles to trigger the required expression programs (for example, stabilization of hypoxia-inducible factor 1 − ˛). Unsurprisingly, mitochondrial dysfunction results in wide range of disorders. Understanding how cells adapt to changes in mitochondrial function is critical for the evaluation of mitochondrial disorders and the development of potential treatments. Each type of mitochondrial dysfunction results in a unique transcriptional response. Here we review the role of nuclear-encoded factors in the response to changes in mitochondrial function and discuss their relevance to metabolic homeostasis, outlining the diverse and complex ways in which nuclei adapt to maintain mitochondrial homeostasis. This article is part of a Directed Issue entitled: Mitochondrial Diseases. © 2015 Published by Elsevier Ltd.
1. Introduction Organelle facts: - Mitochondrial dysfunction activates regulatory pathways that induce changes in nuclear gene expression able to monitor the organelle status. - Mitochondrial function is connected to cell signaling pathways through changes in redox and phosphate pairs (NAD/NADH; CoQH2/CoQ and ATP/ADP vs. AMP), critical metabolite concentrations (succinate, aK-glutarate, AcetylCoA, etc.), and reactive oxygen species (ROS) production. - Variations in mitochondrial status modulate specific transcriptional programs. - The process that transduces the information required for the cell to adapt to a mitochondrial challenge is called “retrograde signaling”.
夽 This article is part of a Directed Issue entitled: Mitochondrial Diseases. Q2 ∗ Corresponding author at: Centro Nacional de Investigaciones Cardiovasculares Carlos III, Departamento de Desarrollo y Reparación Cardiovascular, Melchor Fernandez Almabro 3, 28029 Madrid, Spain. Tel.: +34 914531200; fax: +34 914531240. E-mail address: [email protected] (J.A. Enriquez).
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Mitochondria are well known for their role of producing energy by oxidative phosphorylation, but these organelles also make critical contributions to other areas of cell metabolism, information flux (calcium, ROS, etc.) and cell-death cascades (apoptosis). The first clinical report of a genuine mitochondrial dysfunction was published by Rolf Luft in 1959 (Ernster et al., 1959). Since then, a number of diseases have been linked to mitochondrial dysfunction, and current figures show that 1 in every 5000 individuals are affected by a mitochondrial disorder (Pfeffer et al., 2012). The wide range of pathologies caused by mitochondrial dysfunction include lactic acidosis, skeletal myopathy, deafness, neurodegenerative diseases, muscular disorders, cardiomyopathy, diabetes and cancer (Vafai and Mootha, 2012). The varied symptoms and the involvement of multiple tissues make mitochondrial disorders hard to diagnose and treat, and diagnosis is best achieved by identifying the underlying genetic alteration. Mitochondrial dysfunction can alter cell signaling because of its primary role in synthesizing critical metabolites (NADH/NAD+ , ATP/ADP, ATP/AMP, succinate/a-ketoglutarate, etc.). Mitochondrial dysfunction can thus affect sirtuin-mediated signaling (NADH/NAD+ ), AMPK signaling (ATP/AMP), mTOR signaling (ATP/ADP) or Hif1a signaling (succinate/a-ketoglutarate), and can
http://dx.doi.org/10.1016/j.biocel.2015.01.026 1357-2725/© 2015 Published by Elsevier Ltd.
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also impact signaling mediated by reactive oxygen species (ROS) or Ca2+ (Jones et al., 2012). Depending on the cell type and type of mitochondrial dysfunction, one or several of these paths might be especially affected. Understanding the detailed signaling response to mitochondrial dysfunctions will help to generate a better understanding of the complex puzzle of mitochondrial disorders. 2. Organelle function
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In addition to these signaling molecules, which monitor cell metabolic status and thus mitochondrial performance, information about mitochondrial quality is also transduced to the cell via specific mitochondria-derived pathways, among which the mitochondrial unfolding protein response (mtUPR) is gaining much attention (Mottis et al., 2014). It has also been suggested that mitochondria-to-nucleus retrograde signaling can be envisioned as a complementary mechanism to these mitochondrial quality control systems (Jazwinski, 2013). Changes in nuclear gene expression to maintain mitochondrial homeostasis are not limited to nuclear-encoded mitochondrial proteins. The retrograde response also changes the global nuclear gene expression pattern. Identifying the components of these changes was the first question to be addressed by research into mitochondria-nuclear interactions in the late 1980s. Communication between the mitochondrial and nuclear genomes was first postulated in 1987 in yeast (Parikh et al., 1987). The first factors implicated in retrograde signaling (including COX VI, CIT2 and RTG proteins) were also identified in yeast (Butow et al., 1988; Jia et al., 1997; Liao et al., 1991; Liu and Butow, 2006; Rothermel et al., 1997) (Table 1). Further analysis of Rtg proteins (Rtg1–3) showed that these proteins are normally present in the cytoplasm and translocate to nucleus upon retrograde signaling (Sekito et al., 2000). Subsequent studies in yeast also characterized more factors and also signaling pathways such as RAS2 and the TOR signaling pathway (Butow and Avadhani, 2004; Kirchman et al., 1999; Liu and Butow, 2006) (Table 1). The TOR pathway has also being linked to Rtg proteins in the context of retrograde signaling (Breitkreutz et al., 2010; Dilova et al., 2004; Dilova et al., 2002; Giannattasio et al., 2005; Komeili et al., 2000). Furthermore, yeast studies have shown that dysfunctional mitochondria inhibit TORC1 (Kawai et al., 2011). These studies were followed by others that examined retrograde signaling in more depth and also in other cell types and organisms. Understanding the conservation of the retrograde response between species is very important and therefore studies different organisms are important, especially regarding the differences in mitochondrial homeostasis between yeast and animal cells, particularly during mitochondrial biogenesis (Heddi et al., 1993; Jazwinski, 2013; Poyton and McEwen, 1996). In mammalian cells, the first proteins implicated in retrograde signaling (Cox-Va, b-actin, myc, GAPDH, EF-1) were characterized after the studies carried out in yeast (Marusich et al., 1997; Wang and Morais, 1997) (Table 1). Several studies subsequently revealed the diverse nature of mammalian retrograde signaling, including activation of NFAT, ATF2, NFKb, MAPK, PKC, Egr-1 and CEBP, and CamKIV-mediated activation of CREB (Amuthan et al., 2002; Arnould et al., 2002; Biswas et al., 1999, 2003; Butow and Avadhani, 2004). It should be noted that NFKb has roles in mitochondrial biogenesis and the response to ROS (Srinivasan et al., 2010).
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2.1. Conservation and diversity in retrograde signaling
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Several microarray analyses in yeast showed that mitochondriato-nucleus communication is not limited to a handful of factors
but is instead a global response alters the expression levels of different sets of genes depending on the type of mitochondrial dysfunction (Epstein et al., 2001; McCammon et al., 2003; Traven et al., 2001). Consistent with the yeast studies, the mTOR pathway has been implicated in retrograde signaling in mammalian cells, confirming the conserved nature of retrograde signaling between species (Komeili et al., 2000; Laplante and Sabatini, 2012). Although the retrograde signaling response has yet to be resolved in full, nuclear response elements commonly involved in mitochondrial dysfunction along with more specific ones have been identified. Genome-wide microarray transcriptome studies have been especially important in identifying genes that are differentially expressed upon mitochondrial dysfunction. These studies had performed using different cell lines; one of the earliest studies used a mtDNA depleted human breast cancer cell line (Delsite et al., 2002). However, there is no consensus in the published data. The type of mitochondrial dysfunction seems to have a strong influence on the observed pattern of nuclear gene expression. This has been shown by comparing the expression profiles of Rho0 (mtDNA-depleted) cells and cells carrying the A3243G mutation, which suggests partially distinct multiple pathways of retrograde signaling (Jahangir Tafrechi et al., 2005). Furthermore, RT-PCR and GeneChip microarray analyses consistently show non-identical gene expression patterns in different Rho0 cells lines (Miceli and Jazwinski, 2005; Mineri et al., 2009). 2.2. Key players in the transcriptional response Nonetheless, some signaling pathways are repeatedly reported to be involved in retrograde signaling: mTOR, NFKB, c-JUN/JNK and RXRA, NFATs, PKC, CamK IV, PI3K/AKT, Sirt1, No/CO (Jones et al., 2012). The importance of these pathways is further supported by the implication of defined transcription factors such as MYC, CREB, CEBP, FOXO-1, Egr-1, NRF-1, TFAM, ATF2, ctBP1, and PGC-1a/PRC (Jones et al., 2012).
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Cells affected by mitochondrial dysfunction have to adapt to the sub-optimal energy metabolism. The most common adaptive response to decreased mitochondrial ATP production is increased glycolytic flux to lactate (von Kleist-Retzow et al., 2007). In yeast, the metabolic adaptation to an incomplete TCA cycle requires production of metabolites such as glutamate (Butow and Avadhani, 2004). Therefore cell survival in these circumstances can be helped by the use of alternative and more varied carbon sources. Common mechanisms observed in yeast are increased glyoxylate cycle activity and fatty acid -oxidation (Jazwinski, 2013), mechanisms also triggered by nutrient deprivation (Wang et al., 2010). In addition, microarray studies of mtDNA-depleted cells revealed that TCA cycle and glyoxylate cycle genes are controlled similarly (Epstein et al., 2001). These metabolic changes in the switch from OXPHOS to glycolysis were corroborated by transcriptomic analysis in Drosophila melanogaster OXPHOS mutants (Freije et al., 2012). However, cells cannot depend solely on glyoxylate cycle for survival, and must therefore activate additional mechanisms. 3.2. Mitochondrial biogenesis, capacity and clearance The purpose of nuclear–mitochondrial cross-talk is to achieve a fine-tuned and functional mitochondrial population. The cell should have the required amount of healthy mitochondria and clear any unhealthy organelles. Mitochondrial quality control is the term usually used to describe the set of events and processes geared
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Table 1 Historical outline of retrograde signaling in yeast and mammals.
Yeast
Mammalian
Significance
Genes & pathways identified
References
Discovery of first factors
RTGs, CIT1, CIT2, COX VI
First signaling pathways
RAS2, TOR
Parikh et al. (1987), Butow et al. (1988), Liao et al. (1991), Rothermel et al. (1997), Sekito et al. (2000) Kirchman et al. (1999), Komeili et al. (2000), Dilova et al. (2002), Butow and Avadhani (2004) Epstein et al. (2001), Traven et al. (2001), McCammon et al. (2003) Marusich et al. (1997), Wang and Morais (1997)
First transciptome studies Discovery of first factors First signaling pathways
-Actin, EF-1, myc, Cox-Va, SD Calcium signaling, CREB signaling, NFK
First transciptome studies
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to achieving optimum mitochondrial homeostasis. The four main events in this process are biogenesis, mitophagy, fusion/fission and movement (MacAskill and Kittler, 2010; Scarpulla, 2011; Youle and Narendra, 2011; Chan, 2012). Mitochondrial biogenesis and fission have been shown to determine the capacity of cells to adapt to respiratory chain dysfunction, and nitric oxide has also been shown to be important for retrograde signaling (Benard et al., 2013). In addition, a major role in the clearance of accumulated proteins from mitochondria is played by the mtUPR (Martinus et al., 1996). The mtUPR is activated in Caenorhabditis elegans upon OXPHOS dysfunction (Haynes and Ron, 2010). Several transcription factors participate in mtUPR activation, including CHOP and CEBP, overlapping TFs associated with retrograde signaling (Horibe and Hoogenraad, 2007). Adjustments to mitochondrial biogenesis and capacity are also triggered by other kinds of cellular stress and upon changes in the metabolic environment. Mitochondrial biogenesis is regulated by nuclear-encoded proteins, transcription factors and co-activators (Scarpulla, 2006, 2011), but also maintains a degree of autonomy (Enriquez et al., 1999). The transcription factors NRF1, NRF2, ERR␣, CREB, and YY1 can regulate the expression of nDNA and, indirectly, mtDNA encoded mitochondrial genes, resulting in adjustments to mitochondrial function and oxidative capacity (Basu et al., 1997; Scarpulla, 2011; Schreiber et al., 2004; Vercauteren et al., 2006). In addition to TFs, an even more important role in mitochondrial biogenesis is played by transcriptional co-activators. The ‘master regulator’ of mitochondrial biogenesis is the widely studied transcriptional co-activator PGC1␣ (Lin et al., 2005; Scarpulla, 2012; Wenz, 2011). The known downstream TF targets of PGC1␣ are PPARs (regulators of fatty acid oxidation), NRF1 and ERR␣ (regulators of mitochondrial biogenesis) (Wenz, 2013). PGC1␣ has two homologues, PGC1B and PRC (PGC1 related co-activator), which have partially overlapping functions (Gleyzer and Scarpulla, 2011, 2013; Scarpulla, 2011). The three PGC factors are induced or activated in response to a variety of cellular stresses. PGC1␣ expression is regulated by other factors, including YY1, mTOR, CREB, PPARs, and p53 (Cunningham et al., 2007; Sahin et al., 2011; Scarpulla, 2008a,b). PGC1␣ activity can also be adjusted by post-translational modification by Akt, p38 MAPK, AMPK and Sirt1 (Canto and Auwerx, 2009; Fan et al., 2004). The three main metabolic changes that regulate PGC1␣ are caloric restriction, ROS and hypoxia (reviewed in detail in Wenz, 2013), with all three cases affecting mitochondrial performance. Regulation of mtDNA gene expression requires proteins encoded by nDNA. Nuclear-encoded TFs needed for mitochondrial transcription are POLRMT, TFB2M, TFAM and MTERFs (Arnold et al., 2012; Peralta et al., 2012). Mitochondrial transcripts are translated in the specific mitoribosomes (see Rorbach and Minczuk, 2012). Mammalian mtDNA encodes for only 13 proteins, all of which are subunits of OXPHOS complexes. All other OXPHOS protein subunit are encoded by nDNA. The co-assembly of OXPHOS subunits into
Biswas et al. (1999, 2003), Amuthan et al. (2001, 2002), Arnould et al. (2002) Delsite et al. (2002), Jahangir Tafrechi et al. (2005), Miceli and Jazwinski (2005)
complexes and supercomplexes is therefore a very intricate process that requires the action of dedicated chaperones (Ghezzi and Zeviani, 2012; Lapuente-Brun et al., 2013; McKenzie et al., 2011; Q4 Mick et al., 2010) (Fig. 1). 4. Organelle pathology The link between mitochondrial dysfunction and disease has led to intense research into the role of mito-nuclear signaling to develop potential treatments (Cerutti et al., 2014; Khan et al., 2014; Pirinen et al., 2014). A recent comparative analysis of tranciptomic data from different species (human, fly, mouse and worm) showed that mitochondrial dysfunction involves the dysregulation of conserved genes involved in the retrograde signaling response (Zhang et al., 2014). Two major human health problems that appear to be tightly linked to alterations in the mito-nuclear signaling are aging-related diseases and cancer (Reeve et al., 2008; Swerdlow, 2009). 4.1. Aging Lifespan studies in C. elegans suggest that mitochondrial-nuclear crosstalk is an important determiner of lifespan, with lifespan extended by increased glyoxylate cycle activity and knock-down of certain respiratory genes (Cristina et al., 2009; Lee et al., 2010; Vanfleteren and De Vreese, 1995). ROS, HIF1-␣ and mtUPR are implicated in these processes and also in the development of neurodegenerative disorders (Durieux et al., 2011; Houtkooper et al., 2013; Lee et al., 2010; Rugarli and Langer, 2012). Lifespan extension phenotypes have also been observed in D. melanogaster with respiratory chain dysfunction (Copeland et al., 2009; Liu et al., 2011), and the role of the mtUPR response has also been demonstrated in mice (Houtkooper et al., 2013). Loss of mitochondrial homeostasis is also linked to neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease (Lin et al., 2002; Simon et al., 2004). 4.2. Cancer A link between mitochondria and cancer has been proposed repeatedly. However, the contribution of mitochondrial dysfunction to invasiveness and transformation remains unresolved (Amuthan et al., 2001, 2002; Guha et al., 2007). Some studies suggest that the metastatic phenotype is affected by mtDNA mutations that lead to depletion of mtDNA as a consequence of increased ROS signaling (Ishikawa et al., 2008; Kulawiec et al., 2009). Retrograde signaling involving both well functioning and dysfunctional mitochondria, has been implicated in cancer. More recent work showed that a metastatic phenotype can result from overloading of the electron transport chain due to excess superoxide production (Porporato et al., 2014). Furthermore, PGC1␣ may also contribute to cancer progression (Jones et al., 2012). In some tumors linked
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Fig. 1. Overview of retrograde signaling. There are at least four types of mitochondrial dysfunction, which lead to the generation of at least five types of signal: ATP/AMP, NADH/NAD+ , ROS, cytosolic Ca2+ , reduction in membrane potential ( ). Activation of signaling (red arrows) triggers changes in nuclear gene expression that promote diverse responses represented by purple arrows
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to mtDNA mutations and associated mitochondrial defects, mitochondrial biogenesis is upregulated in an apparently compensatory mechanism (Gasparre et al., 2011)). 5. Future outlook A comprehensive knowledge of the interconnected roles of mitochondrial quality control and mito-nuclear signaling will provide the key to a better understanding of human health disorders in which mitochondrial dysfunction plays role, from mitochondrial diseases to metabolic syndrome and degenerative diseases. This knowledge can be expected to pave the way to new treatments to achieve better quality of life for people affected by these conditions. Uncited references Laplante, 2012. Acknowledgements
We thank Dr. Concepción Jimenez for technical assistance. 278 Q6 This study was supported by grants from the Ministerio de 279 Economía y Competitividad (SAF2012-1207 & CSD2007-00020), 280 the Comunidad de Madrid (CAM/API1009), the EU (Mitochondrial 281 European Educational Training, MEET: European Commission Sev282 enth Framework Programme, FP7-PEOPLE-2012-ITN MARIE CURIE, 283 grant agreement No. 317433) and the Instituto de Salud Carlos III 284 (FIS grant PI11-00078). The CNIC is supported by the Ministerio de 285 Q7 Economía y Competitividad and the Pro-CNIC Foundation. 277
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