Mitochondrial T3 receptor and targets

Molecular and Cellular Endocrinology xxx (2017) 1e9

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Mitochondrial T3 receptor and targets
rard Cabello a, b Chantal Wrutniak-Cabello a, b, *, François Casas a, b, Ge a b

INRA, UMR 866 Dynamique Musculaire et M
etabolisme, 34060 Montpellier, France Universit
e de Montpellier, UMR 866 Dynamique Musculaire et M
etabolisme, 34060 Montpellier, France

a r t i c l e i n f o

a b s t r a c t

Article history: Received 16 November 2016 Received in revised form 28 January 2017 Accepted 31 January 2017 Available online xxx

The demonstration that TRa1 mRNA encodes a nuclear thyroid hormone receptor and two proteins imported into mitochondria with molecular masses of 43 and 28 kDa has brought new clues to better understand the pleiotropic influence of iodinated hormones. If p28 activity remains unknown, p43 binds to T3 responsive elements occurring in the organelle genome, and, in the T3 presence, stimulates mitochondrial transcription and the subsequent synthesis of mitochondrial encoded proteins. This influence increases mitochondrial activity and through changes in the mitochondrial/nuclear cross talk affects important nuclear target genes regulating cell proliferation and differentiation, oncogenesis, or apoptosis. In addition, this pathway influences muscle metabolic and contractile phenotype, as well as glycaemia regulation. Interestingly, according to the process considered, p43 exerts opposite or cooperative effects with the well-known T3 pathway, thus allowing a fine tuning of the physiological influence of this hormone. © 2017 Elsevier B.V. All rights reserved.

Keywords: Mitochondrial T3 receptor Mitochondria Mitochondrial/nuclear crosstalk Glucose regulation Muscle development

1. Introduction The physiological importance of thyroid hormone, affecting developmental processes, thermogenesis and metabolism is well known since numerous decades. However, the mechanisms involved in these very broad influences remained unknown for a long time. The pioneering studies of Tata et al. (1963) provided the first indications of the occurrence of a pathway initiated at the nuclear level directly or indirectly governing the expression of numerous genes, in agreement with the description of specific T3 binding sites displaying a high affinity for the hormone located in the nucleus. Pascual et al. (1982), using a photo affinity labeled derivative of T3 (PAL T3), demonstrated the occurrence of two different nuclear proteins able to specifically bind T3. These data were confirmed by the identification of two genes encoding two T3 nuclear receptors (Sap et al., 1986; Weinberger et al., 1986) acting as T3-dependent transcription factors after binding to specific sequences located on gene promoters, called T3 responsive elements (TRE) (Lazar, 1993; Suen et al., 1994; Glass, 1994; Harvey and Williams, 2002). In parallel, other studies suggested the occurrence of extra


tabolisme, * Corresponding author. INRA, UMR 866 Dynamique Musculaire et Me 2 place P. Viala, 34060 Montpellier, France. E-mail address: [email protected] (C. Wrutniak-Cabello).

nuclear mechanisms, induced at the cell membrane (Segal, 1989, 1990), more recently confirmed by the work of Davis's team, demonstrating that the avß3 integrin binds T3 and T4 with a very high affinity and stimulates very quickly phosphorylation pathways culminating in the activation of several transcription factors (Bergh et al., 2005; Davis et al., 2005). More recently, Kalyanaraman et al. (2014) reported that a 30 kDa TRa1 membrane protein activates protein kinase GII, Src, ERK and Akt signaling after T3 binding. Moreover, mitochondrial specific T3 binding sites were also described, possibly related to short term influences of thyroid hormone on the organelle activity, occurring in minutes in vivo or in isolated mitochondria, such as a stimulation of mitochondrial respiration, ATP synthesis and transcription of the organelle genome (Sterling and Milch, 1975; Goglia et al., 1981; Hashizume and Ichikawa, 1982; Martino et al., 1986; Enriquez et al., 1999). Interestingly, the sharp accumulation of knowledge concerning T3 nuclear receptors considerably helped the identification of mitochondrial thyroid hormone receptors. In addition, besides the probable multiplicity of thyroid hormone receptors, several studies increased the complexity of this field by suggesting that different iodothyronines could simultaneously act on different pathways. For instance, T4 has been reported to bind to the avß3 integrin or to the p30 TRa1 protein, activating the corresponding signalizations as efficiently as T3 (Bergh et al., 2005; Davis et al., 2005; Kalyanaraman et al., 2014). Furthermore, T4 and rT3 have been shown to affect actin

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polymerization in astrocytes, with consequences on internalization of type II 5’-deiodinase or axon guidance in the developing brain (Farwell et al., 1993; Paul et al., 1996; Leonard and Farwell, 1997), processes not regulated by T3. Also, T2 seems to affect very quickly and efficiently mitochondrial activity (Lombardi et al., 1998), as described in this MCE issue. 2. Identification of mitochondrial thyroid hormone receptors Mitochondria are considered as the major compartment of T3 accumulation in the cell. Indeed, important amounts of the hormone are rapidly internalized in the organelle (Sterling et al., 1984), thus raising the hypothesis that T3 could directly affect mitochondrial activity, as initially reported by Sterling et al. (1977, 1980). The possible occurrence of thyroid hormone receptors in the organelle has been reassessed using photoaffinity labelling of highly purified mitochondrial proteins with PAL-T3 already used to detect T3 nuclear receptors (Horowitz et al., 1988). Two binding proteins were identified with molecular masses of 43 and 28 kDa, respectively located in the mitochondrial matrix and in the inner membrane. In addition, gel shift experiments demonstrated that the 43 kDa protein specifically recognized canonical TRE sequences, thus demonstrating a DNA binding activity similar that reported for thyroid hormone nuclear receptors (Wrutniak et al., 1995). Moreover, Bigler et al. have reported that three truncated forms of the nuclear receptor are generated from the TRa1 mRNA by the use of alternative start sites (Bigler and Eisenman, 1988; Bigler et al., 1992). Among them, two displayed molecular masses very similar that described for mitochondrial T3 binding proteins. Overexpression of these two truncated TRa1 proteins in CV1 cells demonstrated their specific mitochondrial localization (Wrutniak et al., 1995). In addition, this study also established that overexpression of the 43 kDa protein (p43) strongly stimulates mitochondrial activity and induces an astonishing increase in mitochondriogenesis (Wrutniak et al., 1995; Casas et al., 1999). Since this initial study, several publications have mentioned the occurrence of this protein in mitochondria of different tissues, such as liver, brown adipose tissue, white adipose tissue, red and white muscle, heart or tongue (Wrutniak et al., 1995; Casas et al., 1999; Sato et al., 2006; Morrish et al., 2006; Cvoro et al., 2016), and the occurrence of truncated forms of other nuclear receptors in the organelle, such as glucocorticoid, estrogen, vitamin D, RXRa or PPARg receptors (Scheller et al., 2000; Yager and Chen, 2007; Silvagno et al., 2010; Casas et al., 2000, 2003). 3. Functional characteristics of mitochondrial TRa1 receptors Study of the functional domains of p43 and p28 was performed using the accumulating knowledge concerning the TRa1 nuclear receptor (Wrutniak-Cabello et al., 2001). P43 displays an N-terminal deletion suppressing the first nuclear localization signal (NLS) evidenced by Carazo et al. (2012) and Mavinakere et al. (2012) in the A/B domain but still possesses the second NLS of TRa1 located in the hinge region (Baumann et al., 2001). It includes also the integral DNA binding domain, thus explaining that the 43 kDa PAL-T3 labeled protein binds to canonical TRE sequences. Of course, the Cterminal part of p43 is the same that nuclear TRa1, including the dimerization and T3 binding domains. In contrast, p28 displaying a more important N-terminal deletion is devoid of NLS and DNA binding domain (Wrutniak-Cabello et al., 2001). However, a surprising observation is that p43 and p28 do not possess any classical mitochondrial import signal (Von Heijne et al., 1989; Schatz and Dobberstein, 1996; Neupert, 1997; Pfanner and Geissler, 2001). In agreement with this structural analysis, p43 binds T3 with an affinity similar that reported for the TRa1 nuclear receptor

(109 M
1) (Casas et al., 1999). However, p28 affinity is one order greater (1010 M
1) (Pessemesse et al., 2014), but nearest that reported previously for an unidentified 28 kDa T3 binding protein located on the mitochondrial inner membrane (Sterling and Milch, 1975; Sterling et al., 1983). As expected, in gel shift experiments, p43 binds to canonical or natural DNA TRE sequences; interestingly, four TRE-like sequences are detected on the mitochondrial genome (Wrutniak et al., 1998), and are recognized by p43 in gel shift experiments (Casas et al., 1999). However, it remains to test more directly the occupancy of these mitochondrial sequences by p43 using chromatin immunoprecipitation. One intriguing question was the absence of mitochondrial import signals on p43 and p28, needing very acute studies to understand how these proteins could be addressed inside the organelle. Using isolated mitochondria and cell cultures, Carazo et al. (2012) identified two atypical import sequences inducing independently the mitochondrial import of p43 and p28, helices 5 and 10/11 of TRa1, located in the C-terminal part of the two receptors. Indeed, their fusion to a cytosolic protein induced its mitochondrial import. However, the organelle import of p43 and p28 does not occur following the classical mechanism, as it appears to be independent of energy and membrane potential (Casas et al., 1999), as reported for mtTF1 in yeast mitochondria (Sanyal and Getz, 1995; Biswas and Getz, 2002). Although the influence of p28 at the mitochondrial level remains practically unknown, the cellular activity of p43 has been well established. In CV1, QM7 and C2C12 cell lines, as well as in fibroblast primary cultures, p43 strongly stimulates mitochondrial activity and mitochondriogenesis (Wrutniak et al., 1995; Rochard et al., 2000; Grandemange et al., 2005; Seyer et al., 2011). In isolated organelles and only in the T3 presence, this thyroid hormone receptor increases, in less than 5 min, transcription of the organelle genome (Casas et al., 1999); the extent of this stimulation was similar that observed in the same experiment for TFAM, a wellestablished mitochondrial transcription factor. In addition, changes in the ratio mRNA/rRNA are similar that reported for the direct transcriptional influence of T3 at the organelle level (Enriquez et al., 1999). As expected, this transcriptional p43 effect leads to a marked rise in mitochondrial protein synthesis (Casas et al., 1999). Moreover, deletion of the p43 DNA binding domain fully abrogates these influences, clearly suggesting that p43 binding to mitochondrial DNA is involved in these activities (Casas et al., 1999). Another striking result is the characterization of two other truncated forms of nuclear receptors inside the organelle, mtRXR and mtPPAR (Casas et al., 2000, 2003). In agreement with the occurrence of dimerization domains in all these proteins, physical interactions between p43 and mtRXR or mtPPAR induce a significant stimulation of the mitochondrial thyroid hormone receptor activity, thus indicating that the transcriptional mechanism of p43 presents some similarities with that described for nuclear receptors. However, it remains to better understand this transcriptional activity with the knowledge of the integral complex containing these heterodimers. In particular one question to solve is to determine if these heterodimers could interact with TFAM, TFB1M or TFB2M, important members of the organelle transcriptional complex (Gaspari et al., 2004), or directly to the mitochondrial RNA polymerase. 4. Direct physiological influences of the mitochondrial thyroid hormone pathway at the cell level In order to know the direct influence of this pathway at the cell level and to assess its physiological importance, in vitro experiments using cell cultures and in vivo studies in mice depleted of

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p43 or overexpressing this receptor were performed. These two aspects will be successively considered. 4.1. The mitochondrial/nuclear cross talk It is well established that a cross talk between mitochondria and nucleus could affect the expression of a large number of nuclear genes (Poyton and McEwen, 1996), in particular involved in the expression of the mitochondrial genome, or directly encoding mitochondrial proteins. For instance this cross talk targets PGC-1a gene expression, an important coactivator controlling the expression of the mitochondrial transcription factor TFAM, as well as different enzymatic subunits of the mitochondrial respiratory chain encoded by nuclear genes (Wu et al., 1999; Puigserver, 2005; Mallon et al., 2005; Scarpulla, 2011). Indeed, several signaling pathways between the organelle and the nucleus have been characterized, not only involved in the maintenance of the organelle activity (Butow and Avadhani, 2004;
s et al., 2016). Mitochondria Guha and Avadhani, 2013; Quiro contain an important pool of calcium, imported inside the organelle according to the mitochondrial membrane potential. Calcium entry in the organelle is mediated by the mitochondrial calcium uniporter, the rapid mode (Ram), and, in heart by a ryanodine receptor located on the mitochondrial inner membrane (Feissner et al., 2009). Calcium efflux occurs through a Naþ dependent Naþ/Ca2þ exchanger and a 2Hþ/Ca2þ exchanger differentially expressed according to the tissue considered (Feissner et al., 2009). It is well established that the organelle calcium uptake and release occur through independent mechanisms, affecting calcium pulses (Pizzo et al., 2012) and consequently the expression of genes regulated by this pathway (Brookes et al., 2004; Biswas et al., 2005). In particular, this process involves activation of the Ca2þ/calmodulin-dependent protein kinases controlling gene expression through phosphorylation of key regulator sites on nuclear transcription factors. These kinases allow discriminating between Ca2þ signals which differ in their spike, frequency, amplitude and duration (Heist and Schulman, 1998). Other targets are involved, such as regucalcin, a calcium binding protein (Yamaguchi, 2013), or calcineurin, a Ca2þ dependent phosphatase activating the transcription factor NFAT (Biswas et al., 2003). Over all, alterations of mitochondrial calcium homeostasis affect the expression of numerous genes such as ATF, NFAT, CEBP/d, CREB and activate phosphorylation pathways through PKC and MAP kinases, with consequences on glucose metabolism, oncogenesis or apoptosis (Biswas et al., 2005). In addition, mitochondria are a major site of reactive oxygen species (ROS) production (Poyton et al., 2009) and mitochondrial biogenesis is sensitive to ROS (Scarpulla, 2012). These oxidative molecules, involved in apoptotic and autophagic pathways (RedzaDutordoir and Averill-Bates, 2016; Dodson et al., 2013), influence re the activity of transcription factors such as AP-1 or NF-kB (Mazie et al., 1999; Dalton et al., 1999). Indeed, the release of H2O2 in the cytosol affects different kinases and phosphatases pathways. Activation of ERK kinases leads to MEF2C phosphorylation which directly increases c-Jun transcription, whereas activation of p38 MAP kinases and JNK inducing c-Jun and ATF2 phosphorylation stimulates the transcriptional activity of these transcription factors (Karin and Shaulian, 2001). In addition, ROS inhibits directly NF-kB binding activity by oxidation of cys-62, as well as by inducing indirect phosphorylation of IkBa leading to inhibition of NF-kB activation. Similarly, oxidation of cysteine 179 of IkBß reduces NF-kB signaling. However, other regulations by ROS could activate the NFkB pathway (Morgan and Liu, 2011). Moreover, mitochondrial activity influences fatty acid pools generating PPAR agonists and therefore the activity of this transcription factor (Georgiadi and Kersten, 2012). Last, the influence of

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the organelle activity on long chain fatty acids affects the expression of genes involved in lipid metabolism or AP2 in human adipocytes (Gremlich et al., 1997; Ailhaud et al., 1994). The influence of p43 on this cross talk has been demonstrated at the cell level. For instance, in human fibroblasts, p43 importantly increases the level of ROS production (Grandemange et al., 2005), and in Xenopus eggs, affects calcium signaling (Saelim et al., 2004). These data clearly suggest that the direct mitochondrial T3 pathway could influence a lot of different physiological processes.

4.2. Direct influence of the p43 pathway at the cell level In agreement with this possibility, the regulation of cell proliferation, differentiation, transformation or apoptosis by this mitochondrial pathway has been established in vitro. In avian or murine myoblast lines, p43 overexpression induces myoblast withdrawal from the cell cycle, an absolute prerequisite for the induction of differentiation, and stimulates terminal differentiation, whereas a block of mitochondrial protein synthesis, a final target of p43 in the organelle, induces exactly the opposite changes (Rochard et al., 2000; Seyer et al., 2006). Several targets leading to this myogenic influence have been identified. C-Myc is a proto-oncogene inducing a very potent inhibition of the irreversible cell cycle arrest leading to a block of myoblast terminal differentiation (Miner and Wold, 1991; Crescenzi et al., 1994; Cabello et al., 2010). By repressing cMyc expression, the p43 pathway relieves this inhibition. Thereafter, through the stimulation of myogenin, a myogenic factor inducing myoblast differentiation, it stimulates this process (Rochard et al., 2000; Seyer et al., 2006). These data could be expanded to other cells, with results suggesting that mitochondrial activity influences also erythrocytes and neuron differentiation (Kaneko et al., 1988; Cordeau-Lossouarn et al., 1991). Another striking influence in myoblasts is the ability of p43 to upregulate calcineurin expression, shown to stimulate myogenic differentiation (Seyer et al., 2011), but also to specifically upregulate Myosin Heavy chain I (MHC-I) expression, a slow twitch contractile myosin, as shown by Chin et al. (1998). Indeed, p43 expression in myoblasts increases MHC-I expression, thus suggesting an involvement in the determination of muscle contractile features. In addition, a surprising amount of p43 is synthesized after overexpression of the TRa1 nuclear receptor in human dermal fibroblasts, leading to a large increase in cellular ROS levels (Grandemange et al., 2005). The resulting oxidative stress induces an increase in the expression of c-Jun and c-Fos proto-oncogenes and inhibits tumor suppressor genes expression such as p53, p21WAF1 and Rb, leading to cell transformation. In addition, a surprising induction of the myogenic factor Myf5 leads to a defective myoblast phenotype. After injection in nude mice, these cells develop a typical rhabdomyosarcoma (Grandemange et al., 2005). Lastly, Saelim et al. (2007) reported that T3 inhibits apoptosis activity mediated by cytochrome c release through its TR mitochondrial receptor in CV1 cells and Xenopus oocytes. These data established that the p43 pathway influences very important physiological aspects, directly at the cell level, including developmental and oncogenic processes through the control of the expression of a large panel of genes, such as myogenic factors, the phosphatase calcineurin, or proto-oncogenes and tumor suppressor genes. In addition, through its ability to increase mitochondrial activity and the expression of MHC-I, it probably confers an oxidative and slow twitch contractile phenotype in the large muscle tissular mass, thus favoring the use of lipids as energetic substrate. The detection of p43 in adipocytes precursors also suggests a metabolic and developmental importance of this receptor in adipose tissue (Cvoro et al., 2016).

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5. In vivo influences of the thyroid hormone mitochondrial pathway Generation of mice specifically overexpressing p43 in skeletal muscle, or displaying a general depletion of this receptor, allowed to assess the in vivo importance of the mitochondrial thyroid hormone pathway. A particular attention has been drawn on muscle phenotype and on glycemia regulation. 5.1. Muscle phenotype In two months old mice, as expected from in vitro studies, skeletal muscle p43 overexpression has been shown to stimulate mitochondrial transcription, respiration, respiratory chain activity and ROS production (Casas et al., 2009). This initial activation of the organelle activity clearly affects the mitochondrial/nuclear cross talk, by upregulating the expression of the nuclear coactivator PGC1a (Casas et al., 2008), considered as a major factor increasing mitochondrial biogenesis (Fernandez-Marcos and Auwerx, 2011). In agreement with Wu et al. (1999), this rise leads to a stimulation of the expression of nuclear transcription factors NRF1 and NRF2 and of genes involved in mitochondrial DNA transcription such as TFAM and TFB2M (Casas et al., 2008). As well established, NRF1 and NRF2 induce the transcription of numerous nuclear genes encoding mitochondrial proteins (Kelly and Scarpulla, 2004; Scarpulla et al., 2012). Furthermore, in addition to the organelle transcriptional activity of p43, the increase in TFAM and TFB2M also stimulates the expression of all subunits of the respiratory chain encoded by the mitochondrial genome, leading to a proper mitochondrial biogenesis (Casas et al., 2008). However, during ageing, the permanent oxidative stress generated by p43 overexpression leads to a progressive degradation of mitochondrial activity and to muscle atrophy linked to upregulation of two muscle-specific ubiquitin ligase E3, Atrogin-1/MAFbx and MuRF1, involved in muscle proteolysis (Casas et al., 2009). Also in agreement with in vitro data, p43 overexpression considerably affects muscle contractile properties (Casas et al., 2008). However, this influence differs according to the type of muscle considered. In the oxidative slow twitch soleus muscle, p43 increases the expression of MHC-I as shown in myoblasts (Seyer et al., 2011) and decreases the expression of the fast myosin MHC-II. This results in the replacement of fast MHC-II fibers by slow MHC-I ones. However, in the fast twitch gastrocnemius muscle, MHC-I expression is not affected by p43. Instead of that, expression of MHC-IIa and MHC-IIx myosin isoforms is upregulated whereas MHC-IIb expression, the fastest myosin isoform, is considerably decreased. This differential regulation according to the contractile feature of muscles remains unclear. As p43 stimulates MHC-I expression in cultured myoblasts in the absence of innervation, and in vivo in soleus muscle, the well-established differences in innervation concerning slow and fast twitch muscles could play a major role in the expression of myosin isoforms (Gundersen, 1998; Hughes, 1998), blunting the direct p43 influence on MHC-I expression. Experiments of crossed innervation are in agreement with such a possibility (Dias and Simpson, 1974; Feng et al., 1982; Pette, 1992; Bacou et al., 1996; Barjot et al., 1998). However, although targeting different myosin isoforms, stimulation of the mitochondrial thyroid hormone pathway induces a muscle metabolic and contractile shift toward a slower/more oxidative phenotype (Casas et al., 2008); this suggests that this regulation plays a major role in the permanent association between oxidative and slow twitch contractile features of muscles. These changes could be related to the upregulation of calcineurin expression by p43 (Seyer et al., 2011) stimulating PGC-1a activity (Lin et al., 2002; Meissner et al., 2001) and thus favoring a slower contractile activity (Lin et al.,

2002). Importantly, as p43 increases MHC-I expression in the C2C12 myoblast line, this influence occurs directly at the cell level. The general depletion of p43 induces exactly the opposite changes than that observed in mice overexpressing p43, with a reduction of mitochondrial activity (Pessemesse et al., 2012). Muscle phenotype was characterized by changes in myosin isoforms expression in slow and fast twitch muscles exactly reverse to that recorded in p43 overexpressing mice, underlining that the regulation of MHC-I expression by p43 is restricted to slow twitch muscles. In addition, as it is well established that the size of glycolytic fibers are more important than that of oxidative fibers, the shift toward a glycolytic phenotype observed in p43-/- mice leads to an increased muscle mass (Pessemesse et al., 2012). All these data lead to the conclusion that the mitochondrial thyroid hormone pathway, through its p43 receptor, is involved in the determination of the contractile and oxidative muscle phenotype, inducing changes in the ability of this important tissular mass to use energetic substrate. 5.2. Glycemia regulation This aspect was only studied in p43-/- mice, and provided several interesting results. First, since five month of age, p43-/- animals displayed a lower body weight than control mice and were significantly leaner, despite a higher food intake, in association with a higher metabolic rate (Pessemesse et al., 2012; Bertrand et al., 2013). Although no clear explanation is given for these phenomena, similar data have been reported in TRa0/0 mice, lacking all isoforms encoded by the Thra gene (Pelletier et al., 2008), thus suggesting that p43 is directly at the origin of this phenotype. In addition, despite plasma glucose levels were not altered in p43-/- mice up to 18 months of age after fasting or refeeding, hyperglycemia occurred in oldest p43-/- mice, in association to the development of glucose intolerance and insulin resistance (Bertrand et al., 2013). Such data suggest that p43 depletion could potentiate the development of type-2 diabetes frequently observed during ageing. In addition, when fed a high fat/high sucrose diet, younger p43 depleted animals displayed a severe glucose intolerance linked to a failure of insulin to respond to a glucose overload or to feeding (Blanchet et al., 2012). These observations suggest that p43 depletion does not affect glycemia regulation in normal conditions, but impairs the adaptability of this regulation to adverse conditions such as high caloric diets intake or ageing. Another striking influence of p43 depletion is that plasma insulin levels are higher than that recorded in control mice during fasting, but are insensitive to feeding or to a glucose overload, and consequently become lower than in control animals in these last conditions (Blanchet et al., 2012). Studies performed on isolated pancreatic islets from normal and p43-/- mice produced exactly the same results in response to a glucose overload. Theses abnormalities are associated to an unexplained reduction of pancreatic islet density and area (Blanchet et al., 2012). However, these defects in insulin secretion could be explained by the decreased expression of the glucose carrier Glut2, reducing glucose entry in pancreatic islets and therefore insulin response to feeding or to a glucose overload. In addition, p43 depletion also reduces the expression of the subunit Kir6.2 of the ATP sensitive channel (Blanchet et al., 2012), thus possibly leading to a reduction of the number of functional channels, cell depolarization, opening of voltage dependent calcium channels inducing a higher insulin release in fasted conditions. This possibility well agrees with reports indicating that mutation of this subunit of the ATP sensitive potassium channel results in severe abnormalities in glycemia control and sensitivity to insulin (Huopio et al., 2002; Minami et al., 2004). All these data, in conjunction with the studies of Lowell and

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Shulman (2005), clearly indicates that mitochondria exert a potent influence on the regulation of blood glucose, and, consequently that the p43 thyroid hormone pathway could regulate the glucidic metabolism, not only by activating the oxidative capacity of the organelle. 5.3. Thermogenesis and circulating thyroid hormone levels Additional data were also obtained concerning the in vivo influence of p43 in mice. Whereas body temperature was increased in p43 overexpressing mice, it was decreased in p43 null animals in a normal environment (Casas et al., 2008; Bertrand-Gaday et al., 2016). However, in contrast to TRa invalidation (Pelletier et al., 2008), p43 depletion did not induce cold hypersensitivity, leading to conclude that whereas the mitochondrial thyroid hormone pathway could be involved in the determination of the set point in temperature regulation, the nuclear pathway could regulate adaptive thermogenesis (Bertrand-Gaday et al., 2016). In addition, considering plasma thyroid hormone levels, reduced T3 levels were observed in p43 overexpressing mice, due to a down regulation of Deiodinase 2 expression (Casas et al., 2008). In contrast T4 and T3 levels were higher in p43 null animal than in wild type mice (Blanchet et al., 2012). This influence of the mitochondrial T3 pathway on circulating thyroid hormone levels is presently not understood but could affect a part of the general phenotype observed in these animals, such as glycemia regulation. Although in vitro experiments concerning MHC-I expression clearly establish that this p43 regulation occurs directly at the cell level and independently of thyroid hormone, changes in iodothyronine levels have to be kept in mind during new refined analyses of these phenotypes. 6. Comparison between the physiological influences of mitochondrial and nuclear thyroid hormone pathways Numerous results concerning the TRa1 receptor have been obtained from TRa knockout, or TRa dominant negative knock-in mutant mice (Flamant and Samarut, 2003; Flamant and Gauthier, 2013). In knockout TRa mice, nuclear and mitochondrial TRa isoforms are abrogated, and it is difficult to decipher about the respective influence of each kind of receptor. In TRa dominant negative knock-in mice, one question is put: as observed for TRa1, does expression of this mutant could generate a truncated form able to be addressed into mitochondria, therefore altering the transcriptional p43 influence? The problem is even more complex as the TRa gene generates at least seven different proteins and knock out genetic strategies differently affect the expression of each of them resulting in the observation of different phenotypes (Flamant and Samarut, 2003). Several arguments support the view that p43 and TRa1 could exert opposite regulations. The TRa1 PV knock-in mutation increases T3 levels (Kaneshige et al., 2001), whereas the mutation TRa1L400R does not affect thyroid hormone levels, as observed in TRa-/- mice specifically depleted of TRa1, TRa2 and p43 (Fraichard et al., 1997) in which they are reduced only two days before death. In TRaR348C/R348C dominant negative knock-in mutant mice (Tinnikov et al., 2002), thyroid hormone circulating levels are decreased. However, T4 and T3 blood levels are increased in p43 null mice (Blanchet et al., 2012). Therefore, with one exception which remains to be explained (PV knock-in mutation) and a significant variability, this regulation seems to be differently affected by nuclear and mitochondrial TRa proteins. In the same line, other results demonstrate that the two pathways exert opposite regulations, such as on the regulation of MHC-I expression in soleus muscle, not frequently studied, which is up regulated in TRa1-/-

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mice (Yu et al., 2000) and down regulated in the same muscle in p43 null animals. In contrast, genetic approaches point out similar influences of p43 or TRa depletion on other physiological parameters. For instance, when studied, it appears that p43 and different TRa null mice displays a significant reduction of body temperature (Gauthier et al., 2001; Casas et al., 2008; Pelletier et al., 2008; Bertrand-Gaday et al., 2016), an increased plasma insulin level during fasting and an improvement of insulin sensitivity (Liu et al., 2003; Jornayvaz et al., 2012). These observations suggest that the direct mitochondrial thyroid hormone pathway could play a major role in the involved processes, or at least that the two pathways, through different mechanisms, converge toward a common regulation. The physiological complementarity between the two pathways is also clearly suggested by different studies. The best example is probably the regulation of mitochondriogenesis. P43 directly stimulates mitochondrial genome expression whereas TRa1, via the control of master genes, such as PGC-1a (Wulf et al., 2008), induces the expression of genes encoding subunits of the respiratory chain subsequently imported in the organelle (Pillar and Seitz, 1997; Weitzel et al., 2003; Sheehan et al., 2004); these two pathways induce a proper mitochondrial biogenesis. In vitro studies concerning the regulation of myoblast differentiation lead to a similar conclusion. Cooperatively, the nuclear receptor induces irreversible cell cycle arrest by inhibiting AP-1 (Jun/Fos) activity in the presence of RXR (Cassar-Malek et al., 1996) and p43 by down-regulating cMyc expression (Seyer et al., 2006). In addition, when comparing T3 myogenic regulation between species, mice myoblast differentiation is stimulated by TRa1 which increases MyoD and myogenin expression after binding to TREs identified in the promoter of these genes, and able, when fused to a reporter gene, to induce a stimulation of its expression by T3 and TRa1 (Muscat et al., 1994; Downes et al., 1993; Carnac et al., 1993). However, in birds, T3 does not influence MyoD expression, but p43 stimulates myogenin expression through a pathway probably involving the mitochondrial/nuclear cross talk (Rochard et al., 2000; Seyer et al., 2006). In addition, p43 displays a very specific influence through another pathway. For instance, Chocron et al. (2012) showed that thyroid hormone could stimulate fatty acids oxidation (FAO) in CV1 cells that lacked endogenous TR receptors, but only when these cells expressed exogenous p43. They also report that a mutant fulllength TRa without a start site for p43 could not be stimulated by T3 to increase FAO. However, according to this study, this metabolic influence is not related to the transcriptional p43 activity, but more probably to an interaction of the receptor with the trifunctional protein stimulating fatty acid oxidation in minutes. Interestingly, these workers have also assessed the influence of a short form of TRb expressed in Xenopus, naturally deleted of the A/B domain, and displaying a strong homology with p43 (86% of identity considering amino acid sequence, Xenopus versus mice). This short receptor is similar to avian TRb0, which is efficiently imported into mitochondria (Casas et al., 1999). As expected, Xenopus TRb1 stimulates also fatty acid oxidation. Over all, these data underline that the transcriptional activity of p43 is not only involved in the mitochondrial influence of this receptor. In addition, they indicate that p43 in all species, or short forms of TRb1 expressed in Xenopus or avian species, exerts very specific metabolic influences relatively to the nuclear receptor. These data suggest that the occurrence of p43 and TRa1 could induce an actual thyroid hormone synergy on different pathways, but also could generate a fine tuning of the hormonal action at the cell or at the organism level.

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7. Conclusions 7.1. Key questions for future investigations Surprising data concerning the cell localization of different TRa1 proteins have been published rising a puzzling question. P43 and p28 are addressed into mitochondria, p30 has been reported to be located in the cell membrane, whereas TRa1 is a nuclear protein. This suggests that TRa1 possesses conflicting addressing signals leading to different localizations. Indeed, nuclear localizations signals (NLS) are well characterized in TRa integral receptors, as well as two mitochondrial import sequences (MIS). In addition, according to Kalyanaraman et al. (2014), Cys254 and/or Cys255 palmitoylations are necessary to address p30 at the cell membrane. However, the integral TRa protein possesses all these signals and is exclusively located in the nucleus. In a first analysis, it seems that two NLS in the presence of other import signals are needed to induce a nuclear localization (TRa1). Deletion of the N-terminal sequence leading to the lack of one NLS in the presence of two MIS (p43) leads to a specific mitochondrial addressing. Of course, deletion of the two NLS in the presence of two MIS (p28) leads to a mitochondrial localization. These observations suggest that the occurrence of the N-terminal NLS plays a major role for the final TRa1 localization. However this hypothesis does not explain why p30 (one NLS, two MIS and two palmitoylation sites) could be exclusively located at the membrane level and not inside mitochondria. We have also to keep in mind the important flexibility of the TRa1 re, 1999), leading to possible different conhinge region (Gigue formations of the protein according to the N-terminal deletion, able to mask or unmask different import signals as discussed by Carazo et al. (2012). This possibility is in agreement with the work of Zhu et al. (2005) reporting that the nuclear viral protein VP22 displays both a nuclear localization signal and a sequence able to drive the mitochondrial import of YFP (Yellow Fluorescent Protein). According to these workers, conformational changes of the protein disrupts functionality of the NLS and induces functionality of the mitochondrial import signal. Clearly, this aspect remains to be acutely studied using all recent conformational technologies. Another aspect concerning the “complementarity” observed between the nuclear and the mitochondrial thyroid hormone pathways in p43 and TRa null mice could result from the natural occurrence of small amounts of p43 in the nuclei in normal animals, acting as TRa1 to stimulate gene expression. All studies performed by our team have not detected p43 in nuclei, even using very high amounts of nuclear proteins. However, overexpression of p43 in cells collected from TRa null mice, followed by chromatin immunoprecipitation to address the presence of this receptor on known nuclear genomic sites, associated to the study of the expression of nuclear genes directly regulated by TRa1 could definitively answer to this question. 7.2. General conclusions In conclusion, the identification of mitochondrial thyroid hormone receptors brings a new clue to better understand the pleiotropic influence of iodinated hormones. Importantly, one gene encodes simultaneously the TRa1 nuclear receptor and p43, and allows an hormonal regulation directed on nuclear gene expression and on mitochondrial activity. In addition, changes in the organelle activity targets the expression of other nuclear genes, through the mitochondrial/nuclear cross talk. Such a regulation enlarges the number of thyroid hormone target genes. Interestingly, after the identification of p43 and p28, different

teams have also identified other members of the nuclear receptor superfamily inside mitochondria, thus indicating the occurrence of a new important mechanism for hormonal regulation involving dual pathways through the expression of receptors addressed to different cell compartments. Briefly, it appears that the physiological importance of the mitochondrial thyroid hormone pathway largely exceeds the initial forecasts. It does not regulate only mitochondrial activity and energy metabolism, by affecting the mitochondrial/nuclear cross talk as demonstrated for myoblast differentiation or oncogenic processes, but also for other physiological events, such as testis development (Fumel et al., 2013). Although the importance of a stimulation of the expression of the mitochondrial genome encoding only 13 proteins by p43 seems to be surprisingly physiologically important, this influence well agrees to the fact that mutations in this small genome induces very acute pathologies. 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Please cite this article in press as: Wrutniak-Cabello, C., et al., Mitochondrial T3 receptor and targets, Molecular and Cellular Endocrinology (2017), http://dx.doi.org/10.1016/j.mce.2017.01.054