Mitochondrial endocrinology Mitochondria as key to hormones and metabolism
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) was found. Interestingly, acute anaerobic exercise (sprint exer-
cise) in young healthy subjects increased irisin levels, whereas chronic exercise of 8 weeks (three times sprint exercise per week) did not. It is important to note that this study solely looked at anaerobic exercise; it is known that aerobic exercise increases PGC1
a to a greater extent than anaerobic exercise ( Handschin and Spiegelman, 2008 ), and this (aerobic) type of exercise would thus be more effective in irisin production. These first human studies question the potential beneficial ef- fects of irisin on metabolic status. However, prospective studies that measure the direct effects of exercise on browning are re- quired, and prospective studies should focus on aerobic exercise protocols. In addition to the physiological release of irisin by exer- cise, the therapeutic use of irisin in human clinical trials should be investigated. 5.2. Natriuretic peptides and brown adipose tissue A recent study showed that the cardiac natriuretic peptides (NPs) are capable of browning white adipocytes from mice and hu- mans ( Bordicchia et al., 2012 ). The cardiac peptides, atrial NP (ANP) and the ventricular form (BNP), are predominantly known for their role in the homeostatic control of blood pressure, by promoting vasodilatation, natriuresis and diuresis, and inhibiting renin and aldosterone release ( Levin et al., 1998 ). Later, these hormones were also found to regulate lipolysis as demonstrated both in vitro as in vivo (
). Natriuretic peptides mediate these lipolytic effects predominantly via the NP receptor A (NPRA), whereas the clearance receptor (NPRC) removes the peptides from the circulation. Binding of the NPs to the guanylyl cyclase receptor NPRA leads to increased cellular cGMP, which stimulates lipolysis by acting on HSL ( Sengenès et al., 2000 ). These lipolytic effects of the NPs were only observed in human WAT, and were thought to be primate specific due to the high expression of clearance recep- tors and a low expression of ‘‘biologically active’’ receptors in other species ( Sengenès et al., 2002 ). This was confirmed in the study by Bordicchia et al. (2012) , in
which primary adipocyte cultures from wildtype mice showed no lipolytic response upon ANP infusion. However, in NPRC knockout mice they did find increased lipolysis in these adipocytes, indicat- ing the inhibitory effects of this clearance receptor. Interestingly, these knockout mice had reduced adipose tissue mass and a more brownish adipose tissue phenotype. In support, brown adipocyte marker genes, such as PRDM16, were elevated in both BAT and WAT (inguinal and epididymal). These results indicated the brown- ing effects on WAT via the NPs. It was then shown that exposing mice to cold (4 ° for 6 h) significantly increased plasma BNP levels, and ANP and BNP mRNA expression in the heart. Furthermore, BNP infusion in mice increased UCP-1 and PGC-1 a mRNA expression in both WAT and BAT ( Bordicchia et al., 2012 ). Altogether, these data demonstrate that the NPs have the capacity to enhance BAT activ- ity and recruitment in mice in vitro and in vivo. Do these NPs exert similar effects in humans? Administering ANP systemically and via a microdialysis probe increased lipolysis in healthy men ( Birkenfeld et al., 2005 ). One functional role for the lipolytic effects of NPs could be substrate supply of fatty acids to the heart and muscle during aerobic exercise ( Moro et al., 2006 ). In addition, it is thought that the NPs are important regulators in postprandial fatty acid oxidation in humans ( Birkenfeld et al., 2008 ). Interestingly, it is known in humans that low NP levels are associated with hypertension, obesity, insulin resistance and diabetes ( Khan et al., 2011; Magnusson et al., 2012 ). Furthermore, weight loss in obese subjects by lifestyle intervention ( Chainani- Wu et al., 2010 ) and bariatric surgery ( Changchien et al., 2011; Chen-Tournoux et al., 2010; St Peter et al., 2006 ) showed that M.J. Vosselman et al. / Molecular and Cellular Endocrinology 379 (2013) 43–50 47
BNP levels are increased after weight loss. Interestingly patients with heart failure who suffer from severe weight loss (cachexia) have increased levels of both forms of NPs ( de Lemos et al., 2003; Tikkanen et al., 1985 ), and elevated energy expenditure lev- els, and it could be suggested that elevated NP levels increase brown adipocyte recruitment and activity leading to elevated EE. Birkenfeld et al. (2005, 2008) showed that ANP infusion increased postprandial energy expenditure, however energy expenditure in the fasted state was not affected. The dosage (25 ng/kg/min) of ANP used by Birkenfeld et al. (2008) increased plasma ANP concen- trations fourfold (approximately 300 pg/mL), which is lower than found in heart failure patients (>500 pg/mL). This relative low dose already affected lipid mobilization and postprandial thermogenesis (and possibly BAT) without causing any adverse effects. Currently, therapeutic use of NPs (carperitide and nesiritide) in patients with acute heart failure and acutely decompensated heart failure is only possible by means of infusion and not orally ( Saito, 2010 ). The potential effect of NPs on browning in humans has been demonstrated in the study of Bordicchia et al., where they tested whether NPs could induce a thermogenic gene program in differ- entiated human multipotent adipose-derived stem (hMADS) cells and subcutaneous adipocytes. Interestingly, both ANP and BNP activated PGC-1 a and UCP-1 expression, induced mitochondrial biogenesis, and increased uncoupled and total respiration. These findings imply the potential role of the NPs in increasing acute thermogenesis and brown adipocyte recruitment in humans. They demonstrated that the mechanism of action of the NP’s share a common downstream target with the adrenergic pathway, namely p38 MAPK. Activation of the p38 MAPK pathway ultimately leads to increased transcription of UCP-1 and PGC-1 a ( Bordicchia et al., 2012
). Moreover, it was shown that ANP treatment of hMADS led to a similar increase in UCP-1, PGC-1 a , and cytochrome c protein levels as shown during b-adrenergic treatment. The authors also found that both the adrenergic and NP’s signaling pathways work additive at very low (physiological) concentrations. The activation pathway of the NPs could therefore play a prominent role in addi- tion to the well-known adrenergic pathway in inducing both short- term as long-term effects on BAT. Currently, this is the only direct evidence of browning effects via NPs in humans and future studies are warranted. 6. Conclusions and perspectives The current global obesity problem is affecting more than 1.4 billion adults of 20 years and older, and strikingly, more than 40 million children under the age of five were overweight in 2010 (WHO). Obesity goes along with increased risk on developing dis- eases such as type 2 diabetes and cardiovascular diseases. Finding strategies to induce weight loss are therefore necessary. Currently, brown adipose tissue is regarded as a potential tissue to tackle obesity due to its great capacity to increase energy expenditure and thereby stimulating weight loss. The rediscovery of functional BAT in humans has resulted in an explosion of BAT studies, espe- cially in rodents, to find potential molecules that could lead to BAT hypertrophy and hyperplasia. It is now clear that a third type of adipocyte exists, the beige adipocyte, which can be recruited within WAT after cold acclimation and long-term adrenergic receptor stimulation. This distinct type of adipocyte has shown to arise from a different lineage as the other two types, although functionally and metabolically seen it is similar to the brown adi- pocyte. Current evidence shows that human BAT is likely com- posed of mainly beige adipocytes. Prospective studies in humans are scarce, mostly because of the difficulties associated with the technique to measure BAT activity (PET-CT). Nevertheless, current studies have shown that cold expo- sure is the most effective in stimulating BAT in humans. Adjusting ambient temperature in public buildings to the lower range of our thermoneutral zone could therefore be a sensible and physiological way to increase thermogenesis by increasing the thermogenic po- tential of BAT. Adrenergic agonists (isoprenaline and ephedrine) have not shown to be effective in BAT activation as high dosages are required. This indicates that pharmacological activation of BAT via the adrenergic part of the SNS is difficult. Furthermore, a major drawback of adrenergic agonists and sympathomimetics is the associated cardiovascular stress. Sympathetic activation via capsinoids could be a way to increase energy expenditure and pos- sibly weight loss (with low risks of adverse events), and the indi- rect evidence of BAT being a mediator is promising. Insulin has been shown to induce glucose uptake in BAT to higher levels than WAT, and comparable to skeletal muscle. However, since perfusion of BAT was absent, it remains unclear whether actual thermogen- esis takes place after insulin stimulation. Interestingly, studies in rodents have shown additional pathways to activate BAT and recruit beige adipocytes. Two of them – irisin and NPs – have recently attracted much attention, but definitive answers in humans are so far lacking. Therefore, the coming years are crucial in finding and testing novel activators of BAT in human clinical trials, but most of all to test the hypoth- esis that activation of BAT may indeed be of importance in the treatment of human obesity. Furthermore, future studies should also reveal if continuous activation of mitochondrial uncoupling in BAT could lead to hyperthermia, as has previously been shown to occur when dinitrophenol was used in humans to obtain weight loss.
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, Rosalba Senese b , 1 , Antonia Lanni b ,
, Fernando Goglia a , ⇑ a Dipartimento di Scienze e Tecnologie, Università degli Studi del Sannio, Via Port’Arsa 11, 82100 Benevento, Italy b Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy a r t i c l e i n f o Article history: Available online 13 June 2013 Keywords: Mitochondrion Thyroid hormone Iodothyronine Thyroid hormone analogue a b s t r a c t Thyroid hormones (TH) have a multiplicity of effects. Early in life, they mainly affect development and differ- entiation, while later on they have particularly important influences over metabolic processes in almost all tis- sues. It is now quite widely accepted that thyroid hormones have two types of effects on mitochondria. The first is a rapid stimulation of respiration, which is evident within minutes/hours after hormone treatment, and it is probable that extranuclear/non-genomic mechanisms underlie this effect. The second response occurs one to several days after hormone treatment, and leads to mitochondrial biogenesis and to a change in mito- chondrial mass. The hormone signal for the second response involves both T3-responsive nuclear genes and a direct action of T3 at mitochondrial binding sites. T3, by binding to a specific mitochondrial receptor and affecting the transcription apparatus, may thus act in a coordinated manner with the T3 nuclear pathway to regulate mitochondrial biogenesis and turnover. Transcription factors, coactivators, corepressors, signaling pathways and, perhaps, all play roles in these mechanisms. This review article focuses chiefly on TH, but also looks briefly at some analogues and derivatives (on which the data is still somewhat patchy). We summarize data obtained recently and in the past to try to obtain an updated picture of the current research position con- cerning the metabolic effects of TH, with particular emphasis on those exerted via mitochondria. Ó 2013 Elsevier Ireland Ltd. All rights reserved. Contents 1. Thyroid hormones and iodothyronines: the general picture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 2. Actions of thyroid hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 2.1. Overview of nuclear pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 2.2. Overview of non-nuclear pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 3. Mitochondria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 3.1. Mitochondrial plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 4. Thyroid hormones and mitochondria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 4.1. Direct way . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 4.2. Indirect ways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 5. Thyroid hormones and mitochondrial energetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 5.1. Uncoupling mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 5.2. Other mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 6. Thyroid hormone derivatives and analogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 6.1. Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 6.2. Analogues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 7. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 7.1. Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 0303-7207/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mce.2013.06.006 ⇑ Corresponding authors. Tel.: +39 0823 274542; fax: +39 0823 274545 (A. Lanni), tel.: +39 0823 274571; fax: +39 0824 23013 (F. Goglia). E-mail addresses: antonia.lanni@unina2.it (A. Lanni), goglia@unisannio.it (F. Goglia). 1 These authors contributed equally to the manuscript. Molecular and Cellular Endocrinology 379 (2013) 51–61 Contents lists available at SciVerse ScienceDirect Molecular and Cellular Endocrinology j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m c e
1. Thyroid hormones and iodothyronines: the general picture The thyroid gland produces two main iodothyronines: 3,5,3 0 ,5
- tetraiodothyronine (thyroxine or T4) and 3,5,3 0 -triiodo- L -thyronine (T3). TH release from the thyroid occurs as part of a feedback mech- anism involving the pituitary–hypothalamic axis. At any given time, most T4 and T3 in the body is bound to transport proteins, with only a small, ‘‘unbound’’ or ‘‘free’’, fraction being biologically active. The functions of these proteins most probably include: (a) ensuring a constant supply of TH to the cells and tissues by prevent- ing urinary loss, (b) protecting the organism against abrupt changes in thyroid-hormone production and/or degradation, and (c) ulti- mately protecting against iodine deficiency. All the circulating T4 is secreted by the thyroid gland, whereas most (about 80%) of the systemic T3 is generated by deiodination of T4 within peripheral tissues. T3 is further deiodinated to yield 3,3 0
Thyroid-hormone deiodination is mediated by three iodothyro- nine deiodinases: type I deiodinase (D1), preferentially expressed in the liver but also present in kidney, thyroid, and pituitary; type II deiodinase (D2), present in the central nervous system, anterior pituitary, brown adipose tissue, and placenta; type III deiodinase (D3), present in the central nervous system, placenta, skin, and fe- tal tissue. For further details on deiodinases, the reader is referred to Orozco et al., 2012; Dentice and Salvatore, 2011; Bianco, 2011 . As mentioned above, T4 is synthesized entirely within the thy- roid, while approximately 80% of T3 is formed by peripheral con- version of T4. Uptake of TH into peripheral tissues is mediated by specific membrane transporter proteins. Several transporter fami- lies have been identified, among which the monocarboxylate transporter (MCT) family deserves special attention. Fourteen members of this family have been recognized so far, but in only 6 of them has a ligand-binding site been identified. MCT8 and MCT10 have been identified as specific TH transporters. However, while MCT8 is currently known to be highly specific only for TH ( Friesema et al., 2003 ), MCT10 also has the ability to carry different types of amino acid [e.g., the carrier polypeptide of various organic anion transporters (OATP1C1, OATP1A2, OPTP1A4)]. Among the OATPs, OATP1C1 is the most interesting for the present purposes because it displays high specificity and affinity for certain iodothy- ronines (especially for T4 and rT3, although not for T3). Moreover, its preferential localization within the endothelium of brain capil- laries suggests that OATP1C1 is important for the transport of TH across the blood–brain barrier ( Mayerl et al., 2012 ). The physiolog- ical roles performed by the TH transporters have been discussed in recent reviews ( Kinne et al., 2011; Visser et al., 2011 ) and so will not be described here any further. 2. Actions of thyroid hormones TH act via two distinct pathways: (1) nuclear pathways and (2) non-nuclear pathways. 2.1. Overview of nuclear pathways At the beginning of the 1960s, Tata and coworkers were the first to show that administration of TH to hypothyroid rats induced an increase in their basal metabolic rate, while the simultaneous injection of an inhibitor of transcription (such as actinomycin-D) inhibited this effect ( Tata, 1963 ). These data implicated the nucleus as the locus for the above action. In other experiments, using iso- lated nuclei, they showed that T3 stimulated DNA-dependent RNA-polymerase activity. Later, Samuels et al. and Oppenheimer et al. identified high-affinity nuclear binding sites for TH, suggest- ing that thyroid hormone nuclear receptors (TR) mediated the effects of T3 ( Tata et al., 1962; Tata et al., 1963; Samuels et al., 1974; Oppenheimer et al., 1974; Bassett et al., 2003 ). In the ensu- ing years, efforts were made to purify the receptors, but the results did not allow detailed investigation of their molecular properties until the simultaneous cloning of the receptors by Sap et al. (1986) and
Weinberger et al. (1986) . In mammals, two genes, TRalpha and TRbeta, encode several thyroid-receptor isoforms (TRalpha1, the two splicing variants TRalpha2 and TRalpha3; TRbeta1, TRbeta2, and TRbeta3, respectively). All TRbeta isoforms retain T3-binding activity, whereas only TRalpha1 of the TRalpha isoforms possesses binding activity. The existence of various iso- forms of TRs raises the question as to whether they have distinct or redundant roles. Their tissue-dependent expressions and devel- opmentally regulated differential expression suggest that they mediate specific isoform-dependent actions. In view of their substantial amino-acid homology with respect to steroid hormone receptors, all TR isoforms are considered to be members of the large superfamily of nuclear receptors that also includes the recep- tors for retinoic acid, vitamin D and peroxisomal proliferator acti- vators. These receptors contain multiple functional domains that include, in particular, a DNA-binding domain (DBD) and a car- boxyl-terminal ligand-binding domain (LBD). The DBD domain contains about 70 amino acids forming two ‘‘zinc fingers’’. This region is highly conserved and interacts with the specific DNA seg- ments known as ‘‘thyroid-hormone response-elements’’ (TREs). T3 receptors are transcription factors: they modulate transcription mainly by binding TREs. In the absence of T3, the TR has an intrin- sic transcriptional repressor function. In most cases, the TRs act as heterodimers with a 9-cis retinoic acid receptor (RXR), but there are also multiple TR complexes that bind to TREs ( Farach-Carson and Davis, 2003 ). In addition to RXR, many other molecules are di- rectly or indirectly functionally associated with TRs (vitamin D3, peroxisome proliferator-activated receptor (PPAR), corepressors, coactivators, etc.). The transcriptional activity of TRs is regulated at multiple levels: by T3 itself; by the type of TRE located on the promoters of T3 target genes; by the developmental- and tissue-dependent expressions of TR isoforms; and by a host of nuclear coregulatory factors (coactivators and corepressors) with T3-dependent activity. Deeper consideration of these mechanisms can be found in some recent reviews ( Oetting and Yen, 2007; Yen et al., 2006; Cheng et al., 2010; Flamant and Gauthier, 2012; Tata, 2012 ).
A number of effects mediated by iodothyronines have been de- scribed for which a binding to TRs can be excluded, and it is cur- rently assumed that these effects involve extranuclear binding sites in several compartments of the cell (including the plasma membrane, the cytoskeleton, the cytoplasm, and mitochondria: for review, see Cheng et al., 2010 ). Unlike the nuclear effects, the extranuclear ones: (i) are independent of thyroid hormone nuclear receptors; (ii) may occur within a short time (seconds to minutes); and (iii) may be mediated by signal-transducing pathways such as cAMP and protein kinases ( Bassett et al., 2003; Farach-Carson and Davis, 2003; Saelim et al., 2004; Axelband et al., 2011 ). Some stud- ies have demonstrated that plasma membrane-initiated actions begin at a binding site on integrin a Vb3, a heterodimer protein that interacts both with extracellular matrix proteins and thyroid hormones ( Bergh et al., 2005; Cody et al., 2007 ). Other molecules – such as stilbene, resveratrol ( Lin et al., 2007, 2008 ), and dihydro- testosterone ( Lin et al., 2009a ) – also bind to this integrin ( Davis et al., 2009 ). Lin et al. (2009b) demonstrated that the hormone- binding domain comprises two binding sites. One site is solely for the binding of T3 and activates the phosphatidylinositol 3-ki- nase (PI3K) pathway, leading to cytoplasm-to-nucleus shuttling 52 F. Cioffi et al. / Molecular and Cellular Endocrinology 379 (2013) 51–61 of TRa1 and to transcription of the hypoxia-inducible factor-1a gene. The second site binds both T3 and T4 and appears to trigger PKC, Ras, Raf1, and MEK, resulting in tyrosine phosphorylation, activation, and nuclear translocation of MAPK ( Lin et al., 2009a; Lin et al., 2009b ; for review, see Cheng et al., 2010 ). It is known that TH affect cellular calcium homeostasis, and this effect is probably due to a nongenomic action. In fact, a recent study on GH3 cells showed that both T2 and T3 exert short-term nongenomic effects on intracellular calcium by modulating plasma-membrane and mitochondrial pathways ( Del Viscovo et al., 2012 ). Those authors showed that nimodipine largely prevented the [Ca 2+ ] i increases elicited by T2 and T3, suggesting that these two iodothyronines share L-type VDCC as a plasma-membrane target. Clear nonge- nomic actions have been reported that involve AMP-activated protein kinase (AMPK) ( Irrcher et al., 2008 ) and Akt/protein kinase B ( Moeller et al., 2005 ). In skeletal muscle in vivo, T3 stimulates both fatty acid and glucose metabolism through rapid activations of the associated signaling pathways involving AMPK and Akt/pro- tein kinase B ( de Lange et al., 2008 ). (For a short summary of nucle- ar/non-nuclear pathways of TH see Table 1
). 3. Mitochondria The evidence that TH affects metabolic rate dates back a long way. However, despite this and the increasing knowledge of the physiology and mechanism of action of TH, several aspects of their effects on metabolic rate (also called calorigenic effects) remain to be elucidated. The existing evidence and the current debate are fo- cused on two possible mechanisms that might underlie the calor- igenic effects of TH: (a) a mechanism involving their interaction with nuclear receptors (TR) and (b) a mechanism involving both TR and/or certain cellular sites such as mitochondria and the cell membrane. Actually, both pathways may have cellular respiration as their ultimate target. Mitochondria, because of their known physiological functions, have been and continue to be the target of most studies on the calorigenic effects of TH. Mitochondria, in fact, provide about the 90% of the cellular energy supply, and they are also the headquarters for a multitude of biochemical pathways related to metabolism (for details, see Fig. 1 ). Indeed, besides ATP synthesis, mitochondria are the site of other important biochemi- cal events such as oxidation of fatty acids, production of free Table 1 Some information about nuclear and non-nuclear pathways of TH actions.(For references see text). Nuclear pathways Non-nuclear signaling pathways Nuclear Thyroid Hormone Receptors (TR): – cAMP-activated protein kinase (AMPK) – TR-
a (TR-
a 1, TR-
a 2 e TR-
a 3) – TR- b (TR-b1, TR-b2 e TR-b3) – TRs act as heterodimers [with i.e.: retinoid X receptor (RXR), peroxisome proliferator-activated receptors (PPARs) and vitamin D3] – Akt/protein kinase B – Corepressor [silencing mediator of TH and retinoid action (SMRT) and nuclear corepressor (NCoR)]
– Phosphatidylinositol 3-kinase (PI3K) – Coactivators [p300, steroid receptor coactivator 1 (SRC-1) and Trip230] – PKC, Ras, Raf1, MEK resulting in activation of mitogen-acti- vated protein kinase (MAPK) Fig. 1. Schematic representation of most of the mitochondrial activities and functions. The respiratory chain transfers electrons from reduced coenzymes [coming from intra (b-oxidation and TCA cycle) – and extra-mitochondrial (glycolysis) oxidative pathways] to O 2 and, pumping out H+ from the matrix to the intermembrane space, generates an electrochemical gradient, D l H+, which provides the driving force for ATP synthesis by FoF1-ATPase. H+ can also enter the matrix by mechanisms not coupled to ATP synthesis either directly, across the lipid bilayer, or indirectly, by protein-mediated transport (mechanism not represented). Phosphate carrier (PiC), ADP/ATP carrier (ANT), and Uncoupling protein (UCP) are represented individually. Mitochondrial calcium uniporter (MCU). Anion carriers (ACs). Translocator Inner Membrane (TIM), Translocator Outer Membrane (TOM), mitochondrial transcription factor A (mtTFA), Apoptosis-inducing factor (AIF). For further details, see text. F. Cioffi et al. / Molecular and Cellular Endocrinology 379 (2013) 51–61 53
radical, heme synthesis, the metabolism of some amino acids, the formation and export of Fe/S clusters, iron metabolism, and cal- cium homeostasis. Very recently, the inner-membrane mitochon- drial calcium uniporter has been identified as the channel responsible for ruthenium-red-sensitive mitochondrial Ca 2+ uptake ( De Stefani et al., 2011 ). In addition, mitochondria contribute to many processes central to both cellular function and dysfunction, including calcium signaling, cell growth and differentiation, cell- cycle control, and cell death. Mitochondria utilize metabolic substrates to generate ATP. Such ATP synthesis, which occurs via ATPase complex, is coupled to oxy- gen consumption via the proton electrochemical gradient existing across the inner mitochondrial membrane. The inner mitochon- drial membrane might be expected to be proton-proof and the mechanism to be tightly coupled, but actually the coupling is not perfect, and the proton flux across the inner membrane that is not coupled to ATP synthesis (the so-called proton leak) dissipates part of the gradient as heat. 3.1. Mitochondrial plasticity Mitochondrial shape and their positioning within cells is crucial and is tightly regulated by processes of fission and fusion, biogen- esis and autophagy, thus ensuring a relatively stable mitochondrial population ( Hailey et al., 2010; Osellame et al., 2012 .) In addition, mitochondria are known to be involved in apoptosis, and some recent data show that they are involved in many other cellular pathways, such as the recently highlighted ones that participate in innate immune responses ( West et al., 2011 ). The number of mitochondria varies according to the function of the cell-type and to the physiological state of the cell/organism. The mecha- nisms underlying mitochondrial turnover (i.e., biogenesis, degradation, autophagy) are now quite well elucidated, at least in some respects. The process of mitochondrial biogenesis requires the coordination of mitochondrial and nuclear genomes. In fact, the mitochondrial proteome includes about 1500 proteins, most of which are coded by the nuclear genome, with only 13 being coded by the mitochondrial genome. Accordingly, the biogenesis, abun- dance, morphology, and physiological properties of mitochondria are regulated primarily by the nuclear genome through a series of transcription factors that regulate the activity of the mitochon- drial genome and the expressions of mitochondrial proteins (see Fig. 2
). In recent decades, our knowledge regarding the dynamics of these organelles has greatly improved. Indeed, the old view of iso- lated mitochondria as static bean-shaped organelles is agonizing and is now replaced by the view of a dynamic and branched net- work moving throughout the cell and undergoing structural transi- tions and changing the shape, morphology, and size. These changes depend on the cell-type and on the cell’s status (for review, see Lie- sa et al., 2009 ). In mitochondria, plasticity and function are interre- lated since plasticity may affect the activity of the organelles, while their function/dysfunction may affect their morphology and dynamics ( Kuznetsov et al., 2009 ). These changes are tightly regu- lated by the balance between ‘‘fusion’’ and ‘‘fission’’, and determine the appearance of the dynamic organelles, their composition, and finally their activities and functions ( Michel et al., 2012 ). The prin- cipal elements participating in these events are: For fusion : – Mitofusin 1 and 2 (MFN1 and MFN2), which are located in the outer mitochondrial membrane and form homo- and hetero- oligomeric complexes between apposing mitochondria ( Koshi- ba et al., 2004; Meeusen et al., 2004; Chen et al., 2005; Detmer Fig. 2. Schematic representation of the TH-dependent nucleus–mitochondrion cross-talk in the regulation of mitochondrial functions (biogenesis, oxygen consumption, and gene expression). Trough active transport or passive diffusion, TH move from outside the plasma membrane into the cytoplasm approaching the extra-nuclear as well as the extra-mitochondrial space. In the cytoplasm, several events can occur, among which deiodination and binding to cytosolic proteins (i.e. cytosolic TH receptors). These can activate signal transduction pathways involving MAPKs, PKC and PI3-K-AKT/PKB. Genomic action requires thyroid hormone responsive elements (TREs) for the recognition of genes for direct transcriptional regulation [a first set of TH target genes (early expression)]. Some of these target genes serve as intermediate factors and regulate a second series of TH target genes (late expression). This group of intermediate factors encompasses transcription factors (NRF-1, NRF-2, PPAR c ) and transcriptional coactivators (PGC- 1 a , PGC-1b). These can ultimately enter the mitochondrion and regulate a second series of T3 target genes [e.g. mitochondrial transcription factor A (mtTFA)]. For further details, see text. 54 F. Cioffi et al. / Molecular and Cellular Endocrinology 379 (2013) 51–61 and Chan, 2007 ). They are mainly involved in the fusion of outer mitochondrial membranes (OMM) and the tethering of mito- chondria to the endoplasmic reticulum (ER) ( de Brito and Scorr- ano, 2009 ). – The dynamin-like GTPase protein OPA1 (optic atrophy type 1), which is located in the intermembrane space (associated with the inner mitochondrial membrane) and mediates the fusion of the inner membranes ( Cipolat et al., 2004; Chen et al., 2005 ). For fission : – Recruitment of Drp1 (a GTPase belonging to the dynamin family) from the cytosol to the OMM. This step is mediated by a mito- chondrial integral outer membrane protein called Fis1 (fission protein 1 homolog) ( Liesa et al., 2009 ). Drp1 oligomerization (regulated by post-translational modification) leads finally to fission (for review, see Chang and Blackstone, 2010 ). During the above mitochondrial processes, there is mitochondrial exchange of such molecules as mtDNA, and proteins, and parts of membranes (for review, see Westermann, 2010 and
Otera and Mihara, 2011 ). Several external stimuli may affect mito- chondrial plasticity, including thyroid hormones; however, to our knowledge there are few or no data on this issue at present. 4. Thyroid hormones and mitochondria Modulation of mitochondrial activity by TH may be effected in one of two ways: direct or indirect. 4.1. Direct way The direct mode requires the presence inside the organelles of specific binding sites for the hormone. In contrast, the indirect one does not need these sites to be present but instead may be mediated by signaling pathways located in different parts of the cell. Concerning the first possibility, the presence of binding sites for T3 has been reported by several laboratories. High-affinity binding sites for T3 in the mitochondrial inner membrane were first reported in 1975 by Sterling and Milch (1975) . The existence of mitochondrial binding sites for T3 were confirmed by others in 1981 ( Goglia et al., 1981 ), but despite this and despite several re- ports of rapid effects of T3 on mitochondria, the physiological sig- nificance of these sites and indeed their very existence, and the physiological significance of the direct effects were controversial at that time. Subsequently, however, the existence of specific mito- chondrial binding sites for T3 received additional confirmation from the work of Morel et al. (1996) and Wrutniak et al. (1995) . Morel et al. studied the kinetics of the internalization and specific subcellular binding of T3 in mouse liver, both in vivo and in vitro. They showed, by quantitative electron microscopic autoradiogra- phy, that after the injection of radiolabeled T3, specific binding was evident in five cell-compartments (including mitochondria). Surprisingly, specific binding was not evident in the cytosol, which contains T3-binding proteins. Wrutniak et al., using a photoaffinity labeling technique, identified two T3-binding proteins in rat liver mitochondrial extracts. One (molecular weight 43 kDa) was lo- cated in the matrix and the other (MW 28 kDa) in the inner mem- brane. These results are in partial agreement with those obtained by Sterling and Milch (1975) and by us ( Goglia et al., 1981 ). The same group ( Wrutniak et al., 1995 ), using antibodies against the two binding domains of c-erbA K1, identified two proteins [mito- chondrial matrix T3-binding protein (p43) and inner mitochondrial membrane T3-binding protein (p28)] whose location and molecu- lar weight were identical to the mitochondrial T3-binding proteins previously described. Bigler et al. (1992) had previously demon- strated that truncated c-erbAK1 proteins are synthesized from the c-erbA mRNA encoding the full-length TR (47 kDa) by means of an internal AUG codon. Using an expression vector provided by these authors, Wrutniak et al. (1995) overexpressed a truncated 43 kDa c-erbAK1 protein in CV1 cells, and then by cyto-immuno- fluorescence experiments demonstrated that this truncated TRK protein is specifically imported into mitochondria. Interestingly, the same authors have identified five sequences highly related to TRE within the rat mitochondrial genome, and they further showed that p43 binds to one of these sequences in the D-loop region, which contains the promoters of the mitochondrial genome. Very recently, the same group ( Carazo et al., 2012 ) described an atypical mechanism for the import of p43 into the mitochondrion and identified the protein sequences involved in its import. Indeed, two alpha helices in the C-terminal part of p43 are actually mito- chondrial import sequences since fusion to a cytosolic protein induces its mitochondrial translocation. Helix 5 drives the atypical mitochondrial import process, whereas helices 10/11 induce a classical import process. The authors further showed that despite its inability to drive any mitochondrial import, the N-terminal re- gion of p43 also plays a permissive role since in the presence of the C-terminal import sequences, different N-terminal regions deter- mine whether the protein is imported or not imported. These re- sults clearly demonstrate that p43 has the ability to function as a T3-dependent mitochondrial transcription factor. The p43 mito- chondrial T3 receptor may perform an important role in skeletal muscle since its depletion adversely affects skeletal muscle devel- opment and activity ( Pessemesse et al., 2012 ). All these data raise the possibility that mitochondrial binding sites for T3 may play very important physiological roles in regulat- ing the mitochondrial transcription apparatus, thus leading to a regulation of mitochondrial biogenesis by acting in synchrony with the nuclear genome. This is an attractive possibility for two rea- sons: (a) T3 influences mitochondrial biogenesis and turnover and (b) the mitochondrial biogenesis or turnover needs the coordinated participation of the nuclear and mitochondrial genetic apparatuses. Actually, early results obtained by us and by others – showing that T3 regulates the mitochondrial population and the mitochondrial nucleic acid level ( Gadaleta et al., 1972; Mutvei et al., 1989; Leo et al., 1976; Goglia et al., 1983 ) – had already suggested just such a possibility. Apparently confirmatory results were obtained by Martino et al. (1986) , who showed a direct action of T3 on mito- chondrial RNA-polymerase in isolated mitochondria, and subse- quently by Enríquez et al. (1999) . The latter authors studied the effect of T3 (both in vivo and in vitro) on ‘‘in organello’’ mtDNA tran- scription and on the ‘‘in organello’’ footprinting patterns in the mtDNA regions involved in the regulation of transcription. Their re- sults confirmed a direct influence of T3 on the mitochondrial tran- scription apparatus, and in particular they showed that T3 selectively modulates the alternative H-strand transcription initia- tion sites without a previous activation of nuclear genes. 4.2. Indirect ways On the basis of the data discussed above, it seems reasonable to conclude that TH have at least three different, but probably interconnected, mode of action, by which they regulate the expres- sions of target genes contributing to mitochondrial biogenesis. The first relies on a binding of TH to nuclear TR, and for TH to affect nu- clear gene expression by binding to a TRE. The second involves TH affecting mitochondrial transcription directly by binding to a mitochondrial TR. In the third, intermediate factors such as the tran- scription factors NRF-1, NRF-2, and PPAR c , and the coactivators PGC-1alpha and PGC-1beta may be synthesized, and by entering the nucleus, regulate other series of TH-target genes. These mecha- nisms may be additionally affected by many nongenomic actions F. Cioffi et al. / Molecular and Cellular Endocrinology 379 (2013) 51–61 55
such as post-translational modifications, by the local bioavailability or by the direct binding of TH to some cellular targets (see Fig. 2 ).
The first member of this family to be identified was PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator 1alpha). PGC-1alpha is rapidly and strongly induced by TH. Indeed, PGC-1
a expression levels and protein levels were increased, respectively, 13-fold ( Weitzel and Iwen 2011 ) and 3-fold ( Irrcher
et al., 2003; Weitzel et al., 2003; Venditti et al., 2009 ) 6 h after administration of T3 and this action is mediated by a TRE in the promoter ( Wulf et al., 2008 ). Besides, recently, Thakran et al. have shown that PGC-1 a partecipates in the T3 induction of CPT1 a and
PDK4 in the liver and, for regulation of hepatic gene expression, PGC-1
a was deacetylated probably through the activation of the nuclear deacetylase SIRT1 ( Thakran et al., 2013 ). It has been shown that PGC-1alpha has profound influences on adaptive thermogen- esis in brown adipose tissue, on hepatic gluconeogenesis, and on mitochondrial biogenesis. In addition, PGC-1alpha coactivates var- ious nuclear receptors and nuclear respiratory factors, including the thyroid hormone receptor ( Puigserver et al., 1998; Sadana et al., 2007; Attia et al., 2010 ). However, PGC-1alpha knock-out mice and knock-down in cell culture have revealed, respectively: few alterations in mitochondrial biogenesis ( Ventura-Clapier et al., 2008; Hock and Kralli, 2009 ) and few defects in TH-mediated gene-expression patterns ( Wulf et al., 2007 ). It is possible that other coactivators of the PGC-1 family may play roles. Recently, the presence of PGC-1alpha has been demonstrated in mitochon- dria. This opens interesting perspectives on the possible roles of these coactivators, but further studies will be needed to undiscover their functions ( Aquilano et al., 2010 ). PGC-1beta, another member of the PGC-1 family, seems to be closely related to PGC-1alpha but there are some differences. PGC-1b, on the other hand, activates mithochondrial biogenesis by binding to different transcription factors (including TR) and its expression has been shown to be rap- idly and strongly induced by TH ( Weitzel et al., 2003 ) suggesting a direct regulation via a TRE. So PGC-1 a and PGC-1b are endoge- nously and rapidly regulated by TH in vivo via a TRE. Other activa- tors regulated by TH include coactivator SRC-1, which plays a role in thermogenesis ( Picard et al., 2002 ). SRC-1 knock-out mice dis- play features of thyroid resistance ( Weiss et al., 1999 ) highlighting a close connection between SRC-1 and TH. These important aspects have been recently reviewed in an excellent and comprehensive manner by Weitzel and Iwen (2011) . Recently, other studies have highlight the clinical relevance of TH. Indeed, recent observation and animal models have shaped our understanding of signaling pathways of thyroid hormone and how this insight might be trans- lated into therapeutic strategies, especially for treating hyperlipid- emia and obesity but also to treat cardiac disease, cancer and improve cognitive function ( Brent, 2012 ). Infact, TR-b mutations have been identified in a broad range of cancer including hepato- cellular carcinoma, renal cell carcinoma, erythroleukemias and thyroid cancer ( Rosen et al., 2011; Chan and Privalsky, 2010 ). In
addition, thyroid hormone acting through TR- a regulates adult hyppocampal neurogenesis which is important in learning, mem- ory and moon ( Desouza et al., 2005; Kapoor et al., 2010 ). 5. Thyroid hormones and mitochondrial energetics It is universally recognized that TH are unique in their ability to stimulate thermogenesis/calorigenesis (the well-known calori- genic effect of TH). Their main action consists in a stimulation of cellular respiration while at the same time reducing metabolic effi- ciency. However, despite this phenomenon being known since the end of the 19th century ( Magnus-Levy, 1895 ) and being the subject of a large number of papers, the mechanism by which TH exert their effects on energy metabolism is far from firmly established. 5.1. Uncoupling mechanism One of the most intriguing hypothesis is the uncoupling hypothesis. This proposes that TH stimulates metabolic rate by act- ing at the mitochondrial level to uncouple the electron transport chain from ATP synthesis. This hypothesis predicts a thyroid- dependent stimulation of energy expenditure without a concomi- tant increase in ATP production (decreased P/O ratio). The early experiments supporting such a possibility were those performed by Lardy and Feldott (1951) and by Hess and Martius (1951) , who showed that mitochondria prepared from T4-treated rats exhibited lower P/O ratios than those from untreated euthyroid controls. However, in the early 1960s its validity was questioned, principally because uncoupling was observed only with pharmaco- logical doses of TH. Since some effects were observable in vitro (in isolated mitochondria), the theory implied that TH acted directly at the mitochondrial level. In addition, the results of such in vitro studies were not always reproducible, and they were widely thought to reflect chemical artifacts. But, this hypothesis has never been dropped, and it continues to this day to be investigated using new approaches. Indeed, it received renewed attention when the discovery was made that uncoupling proteins are present not only in brown adipose tissue (where UCP1, by the mechanism of uncou- pling, is able to dissipate energy, so producing heat), but in almost all tissues and cells, and that their expressions are increased by T3 ( Lanni et al., 1997; Lanni et al., 1999; de Lange et al., 2001 ; for re- view, see also Lanni et al., 2003 and
Cioffi et al., 2009 ). These find- ings stimulated attempts to show a possible involvement of these proteins in the calorigenic effect of T3. In particular, UCP2 (ubiqui- tously expressed) and UCP3 (predominantly expressed in skeletal muscle) have attracted great interest. The realization that UCP3 is present in skeletal muscle, a tissue that is metabolically very active, led to this protein being viewed as a possible candidate for the mediator of the effects of thyroid hormones on resting met- abolic rate. This hypothesis has been investigated and the authors concluded that UCP3 does indeed have the potential to be a molec- ular determinant of the effects of T3 on resting metabolic rate ( de Lange et al., 2001 ). In that study, they showed that when a single injection of T3 was given to hypothyroid rats, a maximal stimula- tion of UCP3 expression was evident at 48 h after the injection. At this time-point, the resting metabolic rate also reached its maximal value and at the mitochondrial level there was a corresponding in- crease in the proton leak. These results received support from the study by Flandin et al. (2009) . In that study, to test the possibility that T3 might act via UCP3, a UCP3-knockout (KO) model was used. This model was found to exhibit a normal phenotype except that upon T3 administration, the stimulation of oxygen consumption was significantly weaker (by 6%) in the UCP3 KO mice than in the wild-type (WT) mice. These results reinforce the idea that UCP3 might play a role in the modulation of energy balance by TH. How- ever, the real uncoupling capacity of UCP3 is under debate, and a question has been raised as to whether the uncoupling effect of UCP3 is a primary function or a secondary one ( Goglia and Skula- chev, 2003 ; and for review, see Azzu et al., 2010 ). 5.2. Other mechanisms Other mechanisms have been proposed to contribute to the uncoupling effect of T3. For instance, a recent study showed that the mitochondrial uncoupling induced by T3 is transduced (in rats in vivo and in cultured Jurkat cells) by a gating of the mitochondrial permeability transition pore (PTP). This T3-induced PTP gating was abrogated in inositol 1,4,5-trisphosphate [IP(3)] receptor1 56 F. Cioffi et al. / Molecular and Cellular Endocrinology 379 (2013) 51–61 [IP(3)R1](À/À) cells, indicating that the endoplasmic reticulum IP(3)R1 may serve as the upstream target for the mitochondrial activities of T3 ( Yehuda-Shnaidman et al., 2010 ). Other mechanisms that may play a role in the calorigenic effects of TH include: (i) the maintenance of transmembrane ion gradients through the action of Na + /K + -ATPase, Ca 2+ -ATPase, and Ca 2+ cycling in muscle and other tissues, as reviewed in a number of articles ( Silva, 2006; Lanni et al., 2001; Silvestri et al., 2005 ) and (ii) regulation of the expres- sions of a selected set of nuclear genes encoding mitochondrial in- ner membrane proteins ( Nelson et al., 1995 ). However, it seems unlikely to us that a rapid regulation of mitochondrial respiration could be achieved by synthesizing respiratory components for insertion into pre-existing membranes. It seems more likely that in the regulation of cellular respiration by TH, a double mechanism operates. One would be a short-term mechanism, useful for a rapid response to sudden physiological changes in energy requirements. The other would be a long-term mechanism, useful for responding to prolonged stimuli (days or weeks) such as a long period of cold exposure or a change in diet or developmental stage. Such a long- term mechanism would ultimately produce a new mitochondrial population that is more or less active (depending on the increased presence of respiratory components) and/or more or less efficient (depending on the increased presence of some specific components, such as UCPs). The action of TH on calcium homeostasis may also play a role in the modulation of mitochondrial energy transduction. 6. Thyroid hormone derivatives and analogues 6.1. Derivatives Until a few years ago, it was a common assumption in the liter- ature that T4 was a precursor, and that T3 was the only active iod- othyronine. However, accumulating evidence suggest that other iodothyronines – such as T4 itself, as well as some metabolites such as reverse T3 (rT3), 3-iodothyronamine (T1AM), and 3,5-T2 (T2) – may be of biological relevance. This issue requires too much space for us to discuss it here in any detail, and since several published re- views have already provided extensive analyses of the available data on these molecules, we will only give a few examples. First, concerning T4 and rT3: Farwell et al. (2006) compared the abilities of iodothyronines to initiate actin polymerization in astro- cytes, and found that T4 and rT3 are each more potent than T3. In addition, they found that acute hormone replacement with either T4 or rT3 completely restored microfilament organization, while acute T3 replacement failed to correct this defect ( Farwell et al., 2006
). Second, concerning T1AM: thyronamines (TAMs) are a recently identified class of endogenous signaling compounds. With the exception that TAMs do not possess a carboxylate group, their structure is identical to that of thyroid hormone and to those of deiodinated thyroid hormone derivatives. The iodothyronamines, which are probably generated by the combined action of deiodin- ases and aromatic amino acid decarboxylase, activate a biogenic amine-like G-protein-coupled receptor (GPCR): namely, trace amine receptor 1 (TAR1). T1AM, which is present both in the blood and in peripheral tissues, seems to have actions opposite to the classic actions of TH; indeed, when injected into mice, T1AM induces rapid falls in body temperature and heart rate. Quite re- cently, it has been shown that T(1)AM has significant physiological effects in mammals, such as reversible, dose-dependent negative inotropic and chronotropic effects on the heart and a cardioprotec- tive effect in perfused rat hearts subjected to ischemia and reper- fusion (
Frascarelli et al., 2011 ). A more exhaustive description of the actions and mechanisms of action of T1AM can be found in a recent review by Piehl et al. (2011) . Third, concerning 3,5-diiodothyronine: until quite recently, this naturally occurring molecule was considered to be an inactive iod- othyronine, but the discovery of metabolic effects of T2 attracted the attention of several group of investigators. Early studies showed that T2 was able to stimulate mitochondrial activities ( Lanni et al., 1992, 1993, 1994; O’Reilly and Murphy, 1992 ); the ef- fects of T2 seem to be mediated by a direct interaction with mito- chondria. Specific binding sites for T2 ( Goglia et al., 1994 b) have been described in rat liver mitochondria, but the data concerning mitochondrial sites need to be interpreted with some caution be- cause of the limitations inherent in such studies. Indeed, due to the inner-ring labeling procedure the 3,5- 125
I-T2 used for the mea- surement of binding parameters had a low specific activity and it was possible to perform studies only over a narrow range of con- centrations. However, subsequent studies ( Lanni et al., 1994; Ar- nold et al., 1998; Goglia et al., 1994a ) showed that addition of T2 to the COX complex isolated from bovine heart stimulated its activity, and suggested that subunit Va of the COX complex might be the binding site for T2 (for review, see Goglia, 2005 ). Effects of T2 have also been observed at the level of the plasma membrane ( Huang et al., 1999; Incerpi et al., 2002 ). Interestingly, we recently succeeded in showing that in rats that had been fed a high-fat diet, administration of T2 stimulated metabolic rate, reduced the serum cholesterol and triglyceride levels, and improved both glucose tol- erance and insulin resistance, effects which involve the well known Sirtuin 1/AMP-activated protein kinase/PGC-1 a pathway ( Lanni et al., 2005; de Lange et al., 2011; Moreno et al., 2011 ,). Similar ef- fects have been observed in humans ( Antonelli et al., 2011 ). How-
ever, whether or not the function of T2 is physiological remains to be elucidated. 6.2. Analogues The metabolic effects of thyroid hormones have long been the focus of research because of the potential use of these hormones as drugs to stimulate body-weight loss and lipid metabolism and to treat some disease such as obesity and diabetes (see Aguer
and Harper, 2012 ). However, the simultaneous induction of delete- rious side effects – such as a thyrotoxic state (tachycardia, muscle wasting, bone loss), and especially those at the cardiac level – effectively stopped TH being used for these purposes. Recently, however, it has been shown that newly discovered analogues and derivatives may have similar desirable effects without the delete- rious side effects. Indeed, since the middle of the last century much effort has been devoted to the development of analogues of thyroid hormones that might improve serum lipid profiles (i.e., plasma cholesterol, lipoprotein, etc.) without having undesirable cardiac effects. In the past few years, the attention of scientists has been focused on the study of agents that are both tissue- and TRb-selec- tive (TRb-receptors are barely expressed in cardiomyocytes), with the principal aim of addressing such major medical problems as obesity, ectopic fat accumulation, and atherosclerosis. Representa- tive analogues endowed with these characteristics are GC-1 (sobet- irome) and KB2115 (or eprotirome). They have the potential to reduce serum LDL cholesterol, lipoprotein (a), and triglyceride lev- els without harmful effects on heart or muscle in humans (for re- view, see Moreno et al., 2008; Baxter and Webb, 2009 ; and Cioffi
et al., 2010; Berkenstam et al., 2008 ). At cellular level, GC-1 is able to stimulate mitochondrial oxidative processes ( Venditti et al., 2010 ). KB2115 also works additively with another cholesterol-low- ering therapy, statins, to produce greater reductions in serum cho- lesterol ( Ladenson et al., 2010 ). However, very recently it has been shown that thyroid hormone receptor b agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity ( Vatner et al., 2013 . This suggest that the development of future TRb agonists must consider the potential adverse effects on insulin F. Cioffi et al. / Molecular and Cellular Endocrinology 379 (2013) 51–61 57
sensitivity. (The structure of TH and its analogues/derivates are shown in
Table 2 ). 7. Conclusions The demands of mitochondria and their complex integration into cell biology extend far beyond the provision of ATP. This has prompted a radical change in our perception of mitochondria, and has made these organelles a major target of investigations into many aspects of cell biology and medicine. The identification of novel mechanisms governing mitochondrial biogenesis and replication, and of the delicately poised signaling pathways coordi- nating the mitochondrial and nuclear genomes, constitute funda- mental steps in in-depth investigations of the role of TH in the modulation of metabolism and of the real involvement of mito- chondria in these actions. TH affect many aspects of mitochondria activity (bioenergetics, transcription, calcium homeostasis, etc.), and thanks to the considerable efforts made by several groups of investigators around the globe, our knowledge of the influence of iodothyronines has grown and grown. 7.1. Perspectives In the future, progress in research into TH and mitochondria may come from investigations using methods such as proteomics. Indeed, mitochondrial proteomics can be a powerful tool in the study of the actions of TH since its coverage can extend to mito- chondrial proteins from all mitochondrial metabolic pathways, including the respiratory chain. Indeed, Silvestri et al. (2010) by combining 2D-E, mass spectrometry, and blue native (BN) PAGE re- cently identified T2-induced mitochondrial proteins that may be responsible for the beneficial effects of T2 on liver adiposity and metabolism. In addition, in the future it should be possible to make progress into the possible use of TH analogues/derivatives to Table 2 Structure of TH derivates/analogues. Thyroid hormones Download 2.44 Mb. Do'stlaringiz bilan baham: 
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