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Thyroid Hormone and Energy Expenditure

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Einav Yehuda-Shnaidman, Bella Kalderon and Jacob Bar-Tana

Submitted: April 12th, 2012 Published: July 18th, 2012

DOI: 10.5772/48309

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1. Introduction

One of the most pronounced effects of Thyroid Hormone (TH, Triiodothyronine (T3), Tetraiodothyronine (T4)) is modulation of metabolic efficiency, energy expenditure and calorigenesis. Thus, hypothyroidism results in decreased energy expenditure and basal metabolic rate accompanied by weight gain and cold intolerance, while hyperthyroidism results in hypermetabolism, weight loss despite increased energy intake, intolerance to heat, loss of lean mass, bone resorption and tachycardia. TH role in modulating metabolic efficiency has been realized for over a century but its cellular mode-of-action remained to be resolved.


2. Mode-of-action of TH in modulating metabolic efficiency

The first description of TH-induced calorigenesis dates to 1895 [1]. That initial report has been followed by exhaustive data focusing on the phenomenology of TH action as reflected by hyper- and hypothyroidsm. Thus, high levels of TH in mammals increase oxygen consumption and heat production, resulting in pronounced body weight loss, while low levels of TH are associated with a decrease in metabolic rate and the oxidation of energy substrates (glucose, fatty acids and amino acids), resulting in pronounced increase in body weight [2-6]. Although it was widely accepted that TH stimulates calorigenesis by affecting respiration, its cellular mode-of-action remained to be resolved. Hence, exhaustive attempts were made by the scientific community throughout the twentieth century to verify the mechanism(s) involved in modulating metabolic efficiency by TH. Studies by Lardy and Feldott [7] and Hess and Martius [8] have pointed out during the 1950s, that the respiratory control ratio of isolated mitochondria was robustly decreased in the presence of added T4. TH was thus claimed to have direct action at the mitochondrial level by inducing ‘mitochondrial uncoupling’, namely, dissociating mitochondrial phosphorylation from its substrate oxidation driver. However, the high T4 doses used in those studies implied possible non-physiological activity rather than authentic TH-induced calorigenesis. Later evidence in support of ‘mitochondrial uncoupling’ has however indicated increase in oxygen consumption and mitochondrial proton permeability of isolated liver mitochondria derived from hyperthyroid rats, with concomitant decrease in mitochondrial phosphate potential and inner mitochondrial membrane (IMM) potential [9, 10]. These observations were further corroborated by increase in liver oxidizing capacity of hyperthyroid rats accompanied by decrease in phosphate and cytosolic redox potential [11], while opposite effects were reported in livers of hypothyroid rats [12]. Similarly, hepatocytes isolated from T3-treated rats show higher oxygen consumption and lower IMM potential as compared with non-treated control [13-16]. Also, a decrease in IMM potential has been reported in TH-treated human lymphocytes or those derived from hyperthyroid patients [17]. Overall, these findings suggested that TH indeed induces mitochondrial uncoupling, and that mitochondrial uncoupling may account for the cellular mode-of-action of TH in modulating metabolic efficiency in vivo.

Concomitantly with the proposed mitochondrial paradigm of TH, others have proposed non-mitochondrial activity of TH in modulating metabolic efficiency. Thus, TH was claimed to induce “futile substrate cycles”, namely, opposing energy-requiring metabolic pathways that proceed simultaneously without generating net products, e.g. glycolysis accompanied by gluconeogenesis, lipolysis with lipogenesis [18, 19], Na+/K+ ATPase with concomitant Na+/K+ leakage [13], or glycerol-3- phosphate/NADH mitochondrial shuttling [20). However, these proposed mechanisms could account for only a small fraction (about 15%) of the total increase in oxygen consumption induced by TH [13, 21], resulting in a mitochondrial paradigm consensus for TH-induced calorigenesis. Yet, the concerned mitochondrial targets still remained enigmatic.


3. Nuclear / mitochondrial targets of TH

TH effects in the mitochondrial context may consist of long-term effects that are dependent upon gene expression, and short-term effects that are refractory to inhibitors of protein synthesis. An important finding reported by Tata et al [2], indicated that the calorigenic activity of TH was abrogated by actinomycin D, implying that TH-induced mitochondrial uncoupling is mediated by modulating nuclear gene expression of respective mitochondrial and/or extra-mitochondrial proteins. These results were followed by extensive studies ([22, 23] and others) that resulted in discovering the nuclear TH receptors (THR) of the superfamily of nuclear receptors, acting as target for TH in modulating nuclear gene expression. THR are encoded by two distinct tissue-dependent genes coding for splice variants of the THRα (brain, bone, heart) and THRβ (liver, brain, heart) isoforms. THR homodimers or heterodimers with other members of the superfamily of nuclear receptors (e.g., retinoic X receptor (RXR)) may interact with TH-response elements (TRE) in the promoters of TH-responsive genes, resulting in transcriptional activation or suppression as function of transcriptional co-activators or co-suppressors recruited by TH/THR to the transcriptional complex of respective promoters. Indeed, TH binding to nuclear THR results in direct transcriptional activation of the expression of genes coding for components of mitochondrial oxidative phosphorylation (i.e. βF1-adenosine triphosphatase, adenine nucleotide translocase (ANT), cytochrome c1) [24, 25], or genes coding for intermediate factors that are indirectly involved in promoting the nuclear expression of mitochondrial components (i.e. nuclear respiratory factors 1 and -2, peroxisome proliferator-activated receptor-γ coactivator-1) [26], or in stimulating mitochondrial DNA replication [27]. Hence, TH-induced mitochondrial uncoupling was believed to be accounted for by TH-induced gene expression of respective protein targets that modulate mitochondrial oxidative phosphorylation. In pursuing putative proteins involved in TH-induced mitochondrial uncoupling, a number of candidates have been suggested. These included the adenine nucleotide translocase, proteins that are involved in phosphatidylglycerol and cardiolipin synthesis [28], and in particular the mitochondrial uncoupling proteins (UCPs).


4. Mitochondrial uncoupling proteins (UCPs)

With the discovery of UCPs, extensive efforts were invested in verifying their putative role in mediating the calorigenic effect of TH. In fact, the UCP-coding genes have TREs in their promoters and their expression level is increased by TH treatment, implying their putative role in mediating TH-induced calorigenesis [40]. UCP1 [29) mediates proton leak in brown adipose tissue IMM [30], resulting in uncoupling fuel oxidation from ATP synthesis and in dissipating IMM potential as heat. The adaptive thermogenic response of UCP1 is driven by the sympathetic nervous system in response to cold temperature or high-energy cafeteria diet, and could apparently serve as target for TH in modulating total body energy expenditure. Indeed, recent findings by Lopez et al [31] have indicated that TH treatment results in suppressing hypothalamic AMP-activated protein kinase (AMPK) activity, resulting in SNS-induced thermogenic response of brown adipose fat. However, UCP1 is specifically expressed in brown adipose tissue, which is sparse in adult humans. While recent findings point to some brown adipose islets in adult humans [32-37], their putative impact on total body energy expenditure still remains to be resolved. Hence, other proteins that share sequence homology with UCP1[38], including the ubiquitously expressed UCP2, and in particular the UCP3 that is expressed in skeletal muscle, were pursued for their role in mediating TH-induced calorigenesis [39]. However, the following observations may indicate that UCP2 and UCP3 may not account for TH-induced mitochondrial uncoupling [41]. Thus, findings suggest that UCP2/3 do not contribute to adaptive thermogenesis [42], but may have a role in ROS signaling [43] and/or in exporting fatty acid anions from the mitochondrial matrix [44]. Also, the expression of liver UCP2/3 proteins is restricted to Kupffer cells, implying that the uncoupling effect of TH in liver parenchymal cells is not due to UCPs. Most importantly, UCP3 knock-out mice are lean and show normal response to TH [45], leaving unresolved the specific proteins that may mediate TH metabolic effects in the mitochondrial context.


5. Mitochondrial permeability transition pore (PTP)

In analogy to UCPs, mitochondria consist of Permeability Transition Pores (PTP) [46-50] located at the contact sites of the inner (IMM) and outer (OMM) mitochondrial membranes. The molecular composition and structure of mitochondrial PTP still remains to be resolved. The current model of PTP consists of the integral proteins ANT (in the IMM), the voltage-dependent anion channel (VDAC, in the OMM), cyclophylin D (CypD, in the mitochondrial matrix) and the Bcl2 family of proteins (in the OMM). PTP gating may present itself in definitive or transient modes, differing in reversibility and synchronization [51, 52]. Definitive synchronized PTP gating is induced by intramitochondrial Ca+2 load [53], and is enhanced by oxidative stress, depletion of adenine nucleotides, increased inorganic phosphate, increased matrix pH, and depolarization of the IMM [54-56]. This opening/gating mode results in high-conductance PTP (HC-PTP), extensive depolarization of the IMM (~70% decrease in IMM potential), rapid passage of ions and solutes of less than 1500 Da across the IMM, and mitochondrial swelling. These may lead to rupture of the OMM, release of mitochondrial proapoptotic proteins (such as cytochrome c, apoptotic intrinsic factor), followed by programmed cell death/apoptosis [57]. Alternatively, spontaneous, non-synchronized, transient/flickering PTP gating due to cyclic opening and closure of individual PTP channels may result in reversible and limited depolarization of the IMM (~30% decrease in IMM potential), moderate decrease in proton motive force, and passage of solutes of less than 300 Da, accompanied by mitochondrial contraction rather than swelling [58-63]. Most importantly, in contrast to the irreversible proapoptotic depolarization inflicted by definitive PTP gating, transient low conductance PTP (LC-PTP) gating is innocuous and reversible, leading to mild mitochondrial uncoupling. These findings may indicate that LC-PTP may serve as mitochondrial target of TH in inducing physiological mitochondrial uncoupling and calorigenesis.


6. Mitochondrial PTP gating by TH

In testing the role played by PTP gating in TH action, a straightforward approach would be to examine whether TH-induced uncoupling is inhibited by the PTP specific inhibitor, cyclosporin A (CSA). CSA acts as a potent inhibitor of PTP gating due to its binding to CypD, resulting in interfering with CypD interaction with PTP-ANT [64, 65]. Indeed, TH-induced lowering of mitochondrial membrane potential and proton gradient followed by mitochondrial swelling are all eliminated by added CSA, pointing to PTP involvement in TH mitochondrial activity [66, 67]. In addition, liver mitochondria of hypothyroid rats show decrease in mitochondrial Ca+2 efflux, swelling and protein release, being restored by TH treatment [68-70]. Furthermore, TH treatment of Jurkat cells induces induce LC-PTP gating [71], implying that mitochondrial PTP may serve as target for TH in inducing mitochondrial uncoupling. However, as described below, TH activity in gating PTP is not accounted for by modulating gene expression of structural components of mitochondrial PTP.

Adenine Nucleotide Translocase (ANT): ANT is a central player in oxidative phosphorylation due to its primary function in translocating adenine-nucleotides via the IMM. ANT function in the PTP context has been verified by its direct association with CypD and VDAC [72], as well as by PTP gating being activated and inhibited by the ANT ligands Atractylate and Bongrekic acid, respectively [73]. Moreover, ANT/CypD/VDAC- reconstituted liposomes show PTP characteristics in terms of sensitivity to Ca+2, CSA and ANT ligands ([74, 75] but see also [76]). Also, over-expression of ANT isoforms (ANT1, ANT3) promotes apoptosis, being inhibited by CSA [77, 78]. Moreover, ANT expression levels affect mitochondrial IMM potential, with high ANT levels resulting in IMM depolarization and mitochondrial proton leak [71, 77, 79]. Hence, in light of ANT structural and regulatory functions in the PTP context, and since the expression level of ANT2, the only ANT isoform expressed in liver, is increased in hyperthyroidism and decreased by hypothyroidism [80], TH-induced ANT expression could apparently account for liver TH-induced LC-PTP gating. However, over-expression of ANT2 in HeLa cell line or in rat primary hepatocytes resulted in extensive mitochondrial depolarization that was not inhibited by CSA [71], implying the formation of PTP-nonrelated ANT channels [81], or of CSA-insensitive PTP [82]. Lack of an obligatory linkage between PTP and ANT conforms to other findings pointing to PTP gating by proapoptotic ligands in liver cells or isolated mitochondria that lack ANT [76].

Cyclophilin D (CypD): CypD is a member of the family of peptidyl-prolyl cis-trans isomerases (PPIase) [83]. The CypD protein contains a mitochondrial-targeting sequence that directs it specifically to the mitochondrial matrix. The link between CypD and PTP has been verified by CypD direct association with ANT [72] as well as by CSA inhibition of PTP gating due to its interaction and inhibition of CypD activity [64, 65, 84]. Moreover, PTP opening by Ca+2 and oxidative stress was enhanced in isolated mitochondria of neurons over-expressing CypD [85], while CSA-sensitive PTP opening was abrogated in isolated mitochondria of CypD knock-out mice [86]. These CypD characteristics may indicate that CypD could apparently serve as protein target of TH in inducing PTP opening and mitochondrial uncoupling. Indeed, liver mitochondria of hyperthyroid rats show increased expression of CypD as well as its PPIase enzymatic activity [71], while opposite effects prevailed in liver mitochondria isolated from hypothyroid rats. However, over-expression of CypD in HeLa cell line, or in rat primary hepatocytes, resulted in mitochondrial hyperpolarization rather than PTP opening [71, 87]. Moreover, over-expressed CypD was found to desensitize cells to apoptotic stimuli or to protect cells from mitochondrial depolarization and apoptosis induced by over-expression of ANT1 [77, 78]. Hence, TH-induced CypD expression may not account for TH-induced PTP gating and calorigenesis. CypD induction by TH may reflect TH activity in inducing peptidyl-prolyl cis-trans isomerase activity and protein folding rather than PTP opening [88].

Voltage Dependent Anion Channel (VDAC): VDAC is a highly abundant protein of the OMM. Its primary function consists of exchanging anions between the cytosol and the inter-membrane mitochondrial space [89]. Previous findings have indicated its putative role in gating mitochondrial PTP [90-94]. However, its expression level is not changed by in vivo TH treatment [71], excluding VDAC from being a molecular target of TH in inducing mitochondrial uncoupling.


7. Modulation of Bcl2-family proteins by TH

The family of Bcl2 proteins consists of more than 20 proteins that were extensively studied in terms of their role in cell death [95]. The Bcl2 family is grouped into two main subfamilies: proapoptotic proteins (e.g. Bax, Bak, and others) and anti-apoptotic proteins (e.g. Bcl2), which promote or inhibit PTP gating, respectively [95-97]. Bcl2-family proteins may directly interact with PTP components such as ANT [98-100] or VDAC [101], and when over-expressed or added to isolated mitochondria may specifically induce (e.g. Bax and Bak) [102-104] or antagonize (e.g. Bcl2) [105] PTP gating. Similarly, depletion of proapoptotic Bax or Bak results in failure of PTP gating [98, 105, 106], whereas Bcl2 inactivation results in definitive PTP gating triggered by oxidative stress [107]. Thus, mitochondrial Bcl2-family proteins and their respective heterodimers (e.g., Bax/Bcl2, Bad/Bcl2) may apparently serve as candidate targets of TH in inducing mitochondrial uncoupling [108-110]. Indeed, TH-induced PTP gating is accompanied by increase in mitochondrial Bax and Bak, together with decrease in mitochondrial Bcl2 content, whereas hypothyroidism results in opposite effects that are reversed by TH [71]. Modulation of the mitochondrial content of Bcl2 proteins by TH is due to their specific translocation in/out of mitochondria, rather than reflecting modulation of their expression and total cellular content. Amplifying the ratio of mitochondrial pro- vs. anti-apoptotic proteins, results in robust decrease in mitochondrial Bax/Bcl2 heterodimer with concomitant increase in free Bax, leading to PTP gating by free mitochondrial Bax [111]. Indeed, over-expression of Bcl2 protects against TH-induced mitochondrial PTP gating [71], implying that depletion of mitochondrial Bcl2 by TH may account for TH-induced mitochondrial uncoupling.


8. Extra-mitochondrial upstream signals that induce TH-induced PTP gating mediated by Bcl2-family proteins

Since Bcl2-Bax hetrodimerization may depend on Bcl2(S70) phosphorylation state [112], mitochondrial Bcl2 depletion by T3 was further verified in terms of Bcl2(S70) phosphorylation profile. Indeed, concomitantly with decrease in mitochondrial Bcl2, T3 treatment results in decreased phosphorylation of monomeric mitochondrial Bcl2(S70) as well as of Bcl2(S70)-Bax heterodimer [113], indicating that mitochondrial Bcl2 depletion may reflect Bcl2(S70) dephosphorylation by TH. In pursuing kinases (e.g. PKA, PKC) or phosphatases (e.g. PP2A, PP2B/Calcineurin) reported to be involved in Bcl2(S70) phosphorylation [112, 114], neither PKA, PKC nor PP2A were found to mediate phosphorylation/dephosphorylation of Bcl2(S70) by TH [113]. In contrast, dephosphorylation of Bcl2(S70) and the depletion of mitochondrial Bcl2 protein by T3 are both reversed by the FK506 inhibitor of PP2B, indicating that the TH effect may be mediated by activation of PP2B [113]. Furthermore, added FK506 blocksT3-induced opening of PTP, indicating that dephosphorylation of Bcl2(S70) and its mitochondrial depletion by T3-activated PP2B may account for mitochondrial PTP opening by TH. Since TH-induced PP2B activation was not accompanied by increase in PP2B expression, PP2B activation was further pursued by searching for TH-induced increase in cytosolic Ca+2 [113]. Indeed, Ca+2 -activated PP2B has previously been reported to bind and dephosphorylate Bcl2(S70) [115, 116]. Most importantly, T3 treatment resulted in pronounced increase in Ca+2, while Ca+2 chelation by BAPTA resulted in abrogating LC-PTP gating by TH, indicating that TH-induced PP2B activity involved mobilization of intracellular Ca+2 [113]. Indeed, T3-induced mobilization of intracellular Ca+2 has recently been reported to mediate a variety of non-genomic effects of TH [117, 118].

The dynamic equilibrium between cytosolic Ca+2 ([Ca+2]c) and endoplasmic reticulum (ER) Ca+2 ([Ca+2]ER) is maintained by an interplay between the inositol 1,4,5-trisphosphate receptor (IP3R1) and the sarcoplasmic Ca+2 ATPase (SERCA) that catalyzes ER Ca+2 efflux and influx, respectively [119]. IP3R1 is activated by binding of the IP3 ligand and may further be modulated by its phosphorylation by PKA, PKC or CaMKII, its dephosphorylation by PP2B, or by its association with one or more of about 50 proteins, including FKBP12 or Bcl2 [120, 121]. The putative role played by IP3R1 in TH-induced PTP gating was evaluated by verifying the effect of TH in cells lacking IP3R1 [113]. Thus, PTP opening, dephosphorylation of mitochondrial Bcl2(S70) and depletion of mitochondrial Bcl2 are all abrogated in cells lacking IP3R1, indicating that IP3R1 is indeed required for TH-induced mitochondrial uncoupling. Similarly, T3 is ineffective in increasing [Ca+2]c upon inhibition of IP3R1 by 2APB, indicating a specific requirement for IP3R1 activity in modulating [Ca+2]c by TH. Furthermore, T3-induced gating of IP3R1 is accounted for by both, increase in IP3R1 expression and protein levels, complemented by IP3R1 truncation into channel-only isoforms. Truncated IP3R1 isoforms have been reported to serve as channel-only peptides capable of carrying out [Ca+2]ER efflux in the absence of added IP3 [122-126]. IP3R1 truncation by TH may reflect TH activation of IP3R1 proteases that remain to be further verified. The IP3R1 / PP2B crosstalk in mediating TH-induced PTP gating is supported by constitutive PP2B-induced PTP gating under conditions of suppressing IP3R1 expression by siRNA [127]. Hence, PP2B is acting downstream to TH-induced IP3R1, and is obligatory as well as sufficient in mediating PTP by [Ca+2]c.

Over all, TH-induced expression of the IP3R1 channel accompanied by its truncation is proposed to result in [Ca+2]ER efflux, increase in [Ca+2]c and [Ca+2]c-activated PP2B, followed by dephosphorylation of mitochondrial Bcl2(S70) with concomitant decrease in mitochondrial Bcl2 protein levels and increase in mitochondrial free Bax (Scheme 1). The decrease in mitochondrial Bcl2 and/or the respective increase in mitochondrial free Bax may initiate and promote variable PTP gating, resulting in physiological LC-PTP–induced calorigenesis. LC-PTP gating may drift to HC-PTP–induced apoptosis as function of additional prevailing conditions that may affect mitochondrial permeability transition.


9. Thyromimetic agents and energy expenditure

Increase in energy expenditure by TH has long been considered for treating obesity. Indeed, treating obesity by thyroid extracts was quite popular throughout the 20th century and well into the 1970s, being later abandoned due to severe side effects consisting of cardiac dysrhythmias, bone resorption / osteoporosis, electrolyte disturbances, and loss of lean body mass [128). Thus, a final ruling warning against the use of thyroid preparations for the treatment of obesity of euthyroid subjects has been issued by the FDA on 1978. Similarly to TH, treating obesity by uncoupling of mitochondrial oxidative phosphorylation by 2,4-dinitrophenol (DNP) has been introduced on 1933, but abandoned on 1938 due to fatal hyperthermia [129].


Scheme 1.

PTP-induced calorigenesis by Thyroid Hormone and MEDICA Analogs

These early attempts were followed by rational drug design of synthetic structural analogs of TH that may avoid the lethal chronotropic cardiac effects of TH, while maintaining the beneficial effects of TH in the context of diseases of the Metabolic Syndrome [130, 131]. Most efforts in that direction were invested in designing thyromimetics that selectively target the liver TH-receptor isoforms (THRβ) while avoiding the heart isoforms (THRα). Tissue selectivity has been further pursued by designing thyromimetics that undergo selective hepatic uptake. These efforts have mainly resulted in thyromimetics effective in treating dyslipidemia, due to increased expression of hepatic LDL-receptors together with CYP7A1 / 7-alpha-cholesterol hydroxylase, resulting in enhancing hepatic uptake of LDL-cholesterol and its conversion into bile. Liver-specific thyromimetics were further found to induce the expression of the hepatic scavenger receptor SR-B1 that mediates reverse cholesterol transport. However, in contrast to the advances made in designing hypolipidemic thyromimetics, the efficacy of thyromimetics in treating obesity and obesity-induced diabetes type 2 still remains to be verified. Moreover, the use of thyromimetics for treating diseases of the Metabolic Syndrome involves potential harmful risks due to: a. The partial selectivity of thyromimetics for hepatic THRβ, resulting in positive chronotropic effects as well as enhanced bone and muscle catabolism induced by high-dose. Hence, the safety of hypolipidemic thyromimetics still remains to be verified in subjects suffering from congestive heart failure or coronary heart disease. b. Since THRβ regulates the feedback loop of hypothalamic TSH, thyromimetics may suppress the production of endogenous TH, resulting in combined hypo- and hyperthyroidsm. These limitations, combined with our present view of the mode-of-action of TH in the mitochondrial context, may however point to an alternative strategy, namely synthesizing thyromimetics that may directly target mitochondrial PTP while avoiding the TH/THR transduction pathway altogether.

Long chain fatty acids (LCFA) have long been shown to induce mitochondrial uncoupling due to their protonophoric activity [81, 132] and/or PTP gating ([51, 133], and ref therein), implying a potential mitochondrial thyromimetic activity. However, the uncoupling activity of LCFA is confounded by their dual role as putative uncouplers of oxidative phosphorylation and as substrates for oxidation or esterification. MEDICA analogs consist of long chain dioic acids (HOOC-C(α′)-C(β′)-(CH2)n-C(β)-C(α)-COOH (n=10-14)) that are substituted in the αα′ or ββ′ carbons [134]. MEDICA analogs may be thioesterified endogenously into their respective mono acyl-CoA thioesters [135], however, they are not esterified into lipids nor β-oxidized, thus dissociating between the substrate role and the putative uncoupling activity of natural LCFA.

Similarly to TH, MEDICA analogs induce calorigenesis in animal models in vivo. Thus, treatment of rats with MEDICA analogs results in an increase in oxygen consumption accompanied by a decrease in liver mitochondrial phosphate potential and cytosolic redox potential, reflecting mitochondrial uncoupling in vivo [136]. Furthermore, treatment of obese leptin receptor-deficient rats (e.g. Zucker, cp/cp) with MEDICA analogs results in increased oxygen consumption and food consumption together with weight loss, implying increased total body energy expenditure [137, 138]. Also, the non-protonophoric mitochondrial activity of MEDICA analogs is similar to that of TH [71], in terms of promoting CSA-sensitive decrease in phosphate and redox potentials with concomitant increase in oxygen consumption in cultured cells as well as in vivo [11, 16, 67, 139, 140], indicating that both MEDICA analogs and TH do converge onto LC/HC-PTP gating [11, 71]. Indeed, similarly to TH, PTP gating by MEDICA analogs is mediated by modulating the profile of mitochondrial Bcl2-family proteins, resulting in decrease in mitochondrial Bcl2-Bax heterodimer with concomitant increase in mitochondrial free Bax [71, 113]. However, different transduction pathways are involved in modulating the mitochondrial content of free Bax by TH or MEDICA analogs. Thus, dissociation of the Bcl2-Bax heterodimer by TH is driven by dephosphorylation of Bcl2(Ser-70) by T3-activated PP2B [113], whereas dissociation of the Bcl2/Bax heterodimer by MEDICA analogs is driven by dephosphorylation of Bad(Ser-112, Ser-155) [141]. The decrease in phosphorylated Bad(Ser-112, Ser-155) results in its decreased binding to14-3-3 followed by its increased binding to mitochondrial Bcl2, resulting in Bax displacement and PTP gating [142, 143]. Decrease in phosphorylated Bad by MEDICA analogs is due to suppression of the Raf1/MAPK/RSK1 and the adenylate cyclase/PKA transduction pathways, and their respective downstream targets Bad(Ser-112) and Bad(Ser-155) [141]. Hence, the TH and MEDICA transduction pathways converge at their downstream Bax target but diverge upstream of the Bcl2/Bax heterodimer (Scheme 1). LC-PTP gating by MEDICA analogs may account for their thyromimetic calorigenic activity in vivo.

10. Conclusion

Energy expenditure by TH has long been realized to be accounted for by uncoupling of mitochondrial oxidative phosphorylation. However, the mode-of-action of TH in promoting mitochondrial uncoupling remained elusive. Mitochondrial uncoupling by TH is transduced by TH-induced gating of mitochondrial PTP due to modulating its Bcl2-family proteins. This mode-of-action underscores the physiological aspects of mitochondrial PTP in modulating metabolic rate, in contrast to most previous studies that analyzed mitochondrial PTP in its apoptotic context. TH-induced gating of mitochondrial PTP may offer a whole new dimension of developing novel anti-obesity drugs that promote weight loss by targeting mitochondrial PTP.


  1. 1. Mittheilung-LK. M.S. Uiiber den respiratorischen Gaswechsel unter dem Einfluss der Thvreoidea so wie unter verschiedenen pathologische Zustandem. Berlin Klin Wochenschr. 32 6506 1895
  2. 2. TataJ. R.ErnsterL.LindbergO. Control of basal metabolic rate by thyroid hormones and cellular function. Nature. 1962Ma Mar 17;193 105860 .
  3. 3. TataJ. R.ErnsterL.LindbergO.ArrheniusE.PedersenS.HedmanR. The action of thyroid hormones at the cell level. Biochem 1963 1963 Mar;86 40828 .
  4. 4. KrotkiewskiM. Thyroid hormones in the pathogenesis and treatment of obesity. Eur J Pharmacol. 2002Ap Apr 12;440(2-3):85-98.
  5. 5. BrunovaJ.BrunaJ.JoubertG.KoningM. Weight gain in patients after therapy for hyperthyroidism. S Afr Med 2003 2003 Jul;93 7 52931 .
  6. 6. Tata JR. The road to nuclear receptors of thyroid hormone. Biochim Biophys Acta. 2012Ma Mar 17.
  7. 7. LardyH. A.FeldottG. Metabolic effects of thyroxine in vitro. Ann N Y Acad Sci. 1951 Dec;54 4 63648 .
  8. 8. HessB.MartiusC. The mode of action of thyroxin. Arch Biochem Biophys. 1951 Oct;33 3 4867 .
  9. 9. Hafner RP, Nobes CD, McGown AD, Brand MD. Altered relationship between protonmotive force and respiration rate in non-phosphorylating liver mitochondria isolated from rats of different thyroid hormone status. Eur J Biochem. 1988De Dec 15;178 2 5118 .
  10. 10. MDBrandSteverding. D.KadenbachB.StevensonP. M.HafnerR. P. The mechanism of the increase in mitochondrial proton permeability induced by thyroid hormones. Eur J Biochem. 1992Ju Jun 15;206 3 77581 .
  11. 11. KalderonB.HertzR.Bar-TanaJ. Effect of thyroid hormone treatment on redox and phosphate potentials in rat liver. Endocrinology. 1992 Jul;131 1 4007 .
  12. 12. Pehowich DJ. Thyroid hormone status and membrane n-3 fatty acid content influence mitochondrial proton leak. Biochim Biophys Acta. 1999Ap Apr 21;1411 1 192200 .
  13. 13. Nobes CD, Lakin-Thomas PL, Brand MD. The contribution of ATP turnover by the Na+/K+-ATPase to the rate of respiration of hepatocytes. Effects of thyroid status and fatty acids. Biochim Biophys Acta. 1989Se Sep 28;976(2-3):241-5.
  14. 14. Shears SB, Bronk JR. The influence of thyroxine administered in vivo on the transmembrane protonic electrochemical potential difference in rat liver mitochondria. Biochem 1979 1979 Feb 15;178 2 5057 .
  15. 15. Gregory RB, Berry MN. The administration of triiodothyronine to rats results in a lowering of the mitochondrial membrane potential in isolated hepatocytes. Biochim Biophys Acta. 1991De Dec 3;1133 1 8994 .
  16. 16. Harper ME, Brand MD. The quantitative contributions of mitochondrial proton leak and ATP turnover reactions to the changed respiration rates of hepatocytes from rats of different thyroid status. J Biol Chem. 1993Ju Jul 15;268 20 1485060 .
  17. 17. al. Effects of thyroid hormones on apoptotic cell death of human lymphocytes. J Clin Endocrinol Metab. 1999 Apr;84 4 137885 .
  18. 18. Shulman GI, Ladenson PW, Wolfe MH, Ridgway EC, Wolfe RR. Substrate cycling between gluconeogenesis and glycolysis in euthyroid, hypothyroid, and hyperthyroid man. J Clin Invest. 1985 Aug;76 2 75764 .
  19. 19. Freake HC, Oppenheimer JH. Thermogenesis and thyroid function. Annu Rev Nutr. 15 26391 1995
  20. 20. Muller MJ, Seitz HJ. Rapid and direct stimulation of hepatic gluconeogenesis by L-triiodothyronine 3 in the isolated-perfused rat liver. Life Sci. 1980 Sep 8;27 10 82735 .
  21. 21. SestoftL. Metabolic aspects of the calorigenic effect of thyroid hormone in mammals. Clin Endocrinol (Oxf). 1980 Nov;13 5 489506 .
  22. 22. OppenheimerJ. H.KoernerD.SchwartzH. L.SurksM. I. Specific nuclear triiodothyronine binding sites in rat liver and kidney. J Clin Endocrinol Metab. 1972 Aug;35 2 3303 .
  23. 23. Samuels HH, Tsai JS. Thyroid hormone action in cell culture: domonstration of nuclear receptors in intact cells and isolated nuclei. Proc Natl Acad Sci U S 1973 1973 Dec;70 12 348892 .
  24. 24. LiR.LuciakovaK.ZaidA.BetinaS.FridellE.BDNelson Thyroid hormone activates transcription from the promoter regions of some human nuclear-encoded genes of the oxidative phosphorylation system. Mol Cell Endocrinol. 1997Ap Apr 4;128(1-2):69-75.
  25. 25. GogliaF.SilvestriE.LanniA. Thyroid hormones and mitochondria. Biosci Rep. 2002 Feb;22 1 1732 .
  26. 26. Weitzel JM, Iwen KA, Seitz HJ. Regulation of mitochondrial biogenesis by thyroid hormone. Exp Physiol. 2003 Jan;88 1 1218 .
  27. 27. Wrutniak-CabelloC.CasasF.CabelloG. Thyroid hormone action in mitochondria. J Mol Endocrinol. 2001 Feb;26 1 6777 .
  28. 28. SchlameM.HostetlerK. Y. Cardiolipin synthase from mammalian mitochondria. Biochim Biophys Acta. 1997Se Sep 4;1348(1-2):207-13.
  29. 29. Nicholls DG, Bernson VS, Heaton GM. The identification of the component in the inner membrane of brown adipose tissue mitochondria responsible for regulating energy dissipation. Experientia Suppl. 32 8993 1978
  30. 30. CannonB.NedergaardJ.Brownadipose.tissuefunction.physiologicalsignificance. Physiol Rev. 2004 Jan;84 1 277359 .
  31. 31. LopezM.VarelaL.MJVazquez-CuencaRodriguez.GonzalezS.VelagapudiC. R.etV. R.alHypothalamic. A. M. P. K.fattyacid.metabolismmediate.thyroidregulation.ofenergy.balance Nat Med. 2010 Sep;16 9 10018 .
  32. 32. NedergaardJ.BengtssonT.CannonB. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E44452 .
  33. 33. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009Ap Apr 9;360 15 15008 .
  34. 34. CypessA. M.LehmanS.WilliamsG.TalI.RodmanD.GoldfineA. al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009Ap Apr 9;360 15 150917 .
  35. 35. VirtanenK. A.MELidellOrava. al. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009Ap Apr 9;360 15 151825 .
  36. 36. ZingarettiM. al. The presence 1 UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. Faseb J. 2009 Sep;23 9 311320 .
  37. 37. al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes. 2009 Jul;58 7 152631 .
  38. 38. RicquierD.BouillaudF. The uncoupling protein homologues: 1 UCP2, UCP3, StUCP and AtUCP. Biochem J. 2000 Jan 15;345 Pt 2 16179 .
  39. 39. LanniA.MorenoM.LombardiA.GogliaF. Thyroid hormone and uncoupling proteins. FEBS Lett. 2003Ma May 22;543(1-3):5-10.
  40. 40. al. Triiodothyronine-mediated up-regulation 2 UCP2 and UCP3 mRNA expression in human skeletal muscle without coordinated induction of mitochondrial respiratory chain genes. FASEB J. 2001 Jan;15 1 135 .
  41. 41. Harper ME, Seifert EL. Thyroid hormone effects on mitochondrial energetics. Thyroid. 2008 Feb;18 2 14556 .
  42. 42. Brand MD, Esteves TC. Physiological functions of the mitochondrial uncoupling proteins 2 and UCP3. Cell Metab. 2005 Aug;2 2 8593 .
  43. 43. PiJ.CollinsS. Reactive oxygen species and uncoupling protein 2 in pancreatic beta-cell function. Diabetes Obes Metab. 2010 Oct;12 Suppl 2 1418 .
  44. 44. SeifertE. L.BezaireV.EsteyC.MEHarper Essential role for uncoupling protein-3 in mitochondrial adaptation to fasting but not in fatty acid oxidation or fatty acid anion export. J Biol Chem. 2008Se Sep 12;283 37 2512431 .
  45. 45. GongD. W.MonemdjouS.GavrilovaO.LeonL. R.Marcus-SamuelsB.ChouC. al. Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3. J Biol Chem. 2000Ma May 26;275 21 162517 .
  46. 46. Halestrap AP, McStay GP, Clarke SJ. The permeability transition pore complex: another view. Biochimie. 2002 Feb-Mar;84(2-3):153-66.
  47. 47. Kinnally KW, Peixoto PM, Ryu SY, Dejean LM. Is mPTP the gatekeeper for necrosis, apoptosis, or both? Biochim Biophys Acta. 2011 Apr;1813 4 61622 .
  48. 48. MiuraT.TannoM.Them. P. T. P.itsregulatory.proteinsfinal.commontargets.ofsignalling.pathwaysfor.protectionagainst.necrosis Cardiovasc Res. 2011De Dec 7.
  49. 49. AzzolinL.vonStockum. S.BassoE.PetronilliV.MAForteBernardi. P. The mitochondrial permeability transition from yeast to mammals. FEBS Lett. 2010Ju Jun 18;584 12 25049 .
  50. 50. ZorovD. B.JuhaszovaM.YanivY.NussH. B.WangS.SollottS. J. Regulation and pharmacology of the mitochondrial permeability transition pore. Cardiovasc Res. 2009Ju Jul 15;83 2 21325 .
  51. 51. KoshkinV.DaiF. F.CARobson-DoucetteChan. C. B.WheelerM. B. Limited mitochondrial permeabilization is an early manifestation of palmitate-induced lipotoxicity in pancreatic beta-cells. J Biol Chem. 2008Ma Mar 21;283 12 793648 .
  52. 52. IchasF.MazatJ. P. From calcium signaling to cell death: two conformations for the mitochondrial permeability transition pore. Switching from low- to high-conductance state. Biochim Biophys Acta. 1998Au Aug 10;1366(1-2):33-50.
  53. 53. BernardiP. Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol Rev. 1999 Oct;79 4 112755 .
  54. 54. ZorattiM.SzaboI. The mitochondrial permeability transition. Biochim Biophys Acta. 1995Ju Jul 17;1241 2 13976 .
  55. 55. PenzoD.TagliapietraC.ColonnaR.PetronilliV.BernardiP. Effects of fatty acids on mitochondria: implications for cell death. Biochim Biophys Acta. 2002Se Sep 10;1555(1-3):160-5.
  56. 56. WieckowskiM. R.BrdiczkaD.WojtczakL. Long-chain fatty acids promote opening of the reconstituted mitochondrial permeability transition pore. FEBS Lett. 2000No Nov 3;484 2 614 .
  57. 57. CromptonM. The mitochondrial permeability transition pore and its role in cell death. Biochem 1999 1999 Jul 15;341 ( Pt 2):233-49.
  58. 58. ZorovD. B.KinnallyK. W.PeriniS.TedeschiH. Multiple conductance levels in rat heart inner mitochondrial membranes studied by patch clamping. Biochim Biophys Acta. 1992Ap Apr 13;1105 2 26370 .
  59. 59. IchasF.JouavilleL. S.MazatJ. P. Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell. 1997Ju Jun 27;89 7 114553 .
  60. 60. JacobsonJ.DuchenM. R. Mitochondrial oxidative stress and cell death in astrocytes--requirement for stored 2 and sustained opening of the permeability transition pore. J Cell Sci. 2002 Mar 15;115(Pt 6):1175-88.
  61. 61. Novgorodov SA, Gudz TI. Permeability transition pore of the inner mitochondrial membrane can operate in two open states with different selectivities. J Bioenerg Biomembr. 1996 Apr;28 2 13946 .
  62. 62. BrustovetskyN.DubinskyJ. M. Dual responses of CNS mitochondria to elevated calcium. J Neurosci. 2000Ja Jan 1;20 1 10313 .
  63. 63. HausenloyD.WynneA.DuchenM.YellonD. Transient mitochondrial permeability transition pore opening mediates preconditioning-induced protection. Circulation. 2004Ap Apr 13;109 14 17147 .
  64. 64. NicolliA.BassoE.PetronilliV.WengerR. M.BernardiP. Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, and cyclosporin A-sensitive channel. J Biol Chem. 1996Ja Jan 26;271 4 218592 .
  65. 65. Griffiths EJ, Halestrap AP. Further evidence that cyclosporin A protects mitochondria from calcium overload by inhibiting a matrix peptidyl-prolyl cis-trans isomerase. Implications for the immunosuppressive and toxic effects of cyclosporin. Biochem 1991 1991 Mar 1;274 ( Pt 2):611-4.
  66. 66. KalderonB.HermeshO.Bar-TanaJ. Mitochondrial permeability transition is induced by in vivo thyroid hormone treatment. Endocrinology. 1995 Aug;136 8 35526 .
  67. 67. HermeshO.KalderonB.BermanB.Bar-TanaJ. Mitochondrial protonophoric activity induced by a thyromimetic fatty acid analogue. Biochim Biophys Acta. 2000Ap Apr 21;1457 3 16674 .
  68. 68. VaccaR. A.MoroL.CaraccioG.GuerrieriF.MarraE.GrecoM. Thyroid hormone administration to hypothyroid rats restores the mitochondrial membrane permeability properties. Endocrinology. 2003 Sep;144 9 37838 .
  69. 69. ChavezE.FrancoM.Reyes-VivasH.ZazuetaC.RamirezJ.CarrilloR. Hypothyroidism renders liver mitochondria resistant to the opening of membrane permeability transition pore. Biochim Biophys Acta. 1998Se Sep 30;1407 3 2438 .
  70. 70. VendittiP.De RosaR.Di MeoS. Effect of thyroid state on susceptibility to oxidants and swelling of mitochondria from rat tissues. Free Radic Biol Med. 2003Se Sep 1;35 5 48594 .
  71. 71. Yehuda-ShnaidmanE.KalderonB.Bar-TanaJ. Modulation of mitochondrial transition pore components by thyroid hormone. Endocrinology. 2005 May;146 5 246272 .
  72. 72. WoodfieldK.RuckA.BrdiczkaD.HalestrapA. P. Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition. Biochem 1998 1998 Dec 1;336 ( Pt 2):287-90.
  73. 73. ASBelzacqBrenner. C. The adenine nucleotide translocator: a new potential chemotherapeutic target. Curr Drug Targets. 2003 Oct;4 7 51724 .
  74. 74. BrustovetskyN.TropschugM.HeimpelS.HeidkamperD.KlingenbergM. A.largeCa2+-dependent.channelformed.byrecombinant. A. D. P. A. T. P.carrierfrom.Neurosporacrassa.resemblesthe.mitochondrialpermeability.transitionpore. Biochemistry. 2002Oc Oct 1;41 39 1180411 .
  75. 75. Haworth RA, Hunter DR. Control of the mitochondrial permeability transition pore by high-affinity ADP binding at the ADP/ATP translocase in permeabilized mitochondria. J Bioenerg Biomembr. 2000 Feb;32 1 916 .
  76. 76. KokoszkaJ. E.WaymireK. G.LevyS. E.SlighJ. E.CaiJ.JonesD. al.TheA. D. P. A. T. P.translocatoris.notessential.forthe.mitochondrialpermeability.transitionpore. Nature. 2004Ja Jan 29;427 6973 4615 .
  77. 77. BauerM. K.SchubertA.RocksO.GrimmS.Adeninenucleotide.translocase-componenta.ofthe.permeabilitytransition.porecan.dominantlyinduce.apoptosis J Cell Biol. 1999De Dec 27;147 7 1493502 .
  78. 78. SchubertA.GrimmS.CyclophilinD. a.componentof.thepermeability.transition-poreis.anapoptosis.repressor Cancer Res. 2004Ja Jan 1;64 1 8593 .
  79. 79. MDBrandPakay. J. L.OclooA.KokoszkaJ.WallaceD. C.BrookesP. al. The basal proton conductance of mitochondria depends on adenine nucleotide translocase content. Biochem 2005 2005 Dec 1;392(Pt 2):353-62.
  80. 80. 1996DummlerK.MullerS.SeitzH. J. Regulation of adenine nucleotide translocase and glycerol 3 -phosphate dehydrogenase expression by thyroid hormones in different rat tissues. Biochem J. 1996 Aug 1;317 ( Pt 3):913-8.
  81. 81. Skulachev VP. Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation. FEBS Lett. 1991De Dec 9;294 3 15862 .
  82. 82. HeL.LemastersJ. J. Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function? FEBS Lett. 2002Fe Feb 13;512(1-3):1-7.
  83. 83. FischerG.Wittmann-LieboldB.LangK.KiefhaberT.SchmidF. X. Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature. 1989Fe Feb 2;337 6206 4768 .
  84. 84. McGee AM, Baines CP. Phosphate is not an absolute requirement for the inhibitory effects of cyclosporin A or cyclophilin D deletion on mitochondrial permeability transition. Biochem 2012 2012 Apr 1;443 1 18591 .
  85. 85. LiY.JohnsonN.CapanoM.EdwardsM.CromptonM.Cyclophilin-Dpromotes.themitochondrial.permeabilitytransition.buthas.oppositeeffects.onapoptosis.necrosis Biochem 2004 2004 Oct 1;383(Pt 1):101-9.
  86. 86. BassoE.FanteL.FowlkesJ.PetronilliV.MAForteBernardi. P. Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J Biol Chem. 2005Ma May 13;280 19 1855861 .
  87. 87. Lin DT, Lechleiter JD. Mitochondrial targeted cyclophilin D protects cells from cell death by peptidyl prolyl isomerization. J Biol Chem. 2002Au Aug 23;277 34 3113441 .
  88. 88. AndreevaL.HeadsR.GreenC. J. Cyclophilins and their possible role in the stress response. Int J Exp Pathol. 1999 Dec;80 6 30515 .
  89. 89. PavlovE.GrigorievS. M.DejeanL. M.ZweihornC. L.CAMannellaKinnally. K. W. The mitochondrial channel VDAC has a cation-selective open state. Biochim Biophys Acta. 2005De Dec 20;1710(2-3):96-102.
  90. 90. CromptonM.VirjiS.DoyleV.JohnsonN.WardJ. M. The mitochondrial permeability transition pore. Biochem Soc Symp. 66 16779 1999
  91. 91. NaritaM.ShimizuS.ItoT.ChittendenT.LutzR. al. Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. Proc Natl Acad Sci U S 1998 1998 Dec 8;95 25 146816 .
  92. 92. al. Identification of the protein-protein contact site and interaction mode of human 1 with Bcl-2 family proteins. Biochem Biophys Res Commun. 2003 Jun 13;305 4 98996 .
  93. 93. RapizziE.PintonP.SzabadkaiG.WieckowskiM. al. Recombinant expression 2 the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria. J Cell Biol. 2002 Nov 25;159 4 61324 .
  94. 94. Abu-HamadS.SivanS.Shoshan-BarmatzV. The expression level of the voltage-dependent anion channel controls life and death of the cell. Proc Natl Acad Sci U S 2006 2006 Apr 11;103 15 578792 .
  95. 95. GrossA.Mc DonnellJ. M.KorsmeyerS. J. B. C. 2 family members and the mitochondria in apoptosis. Genes Dev. 1999 Aug 1;13 15 1899911 .
  96. 96. JacototE.CostantiniP.LaboureauE.ZamzamiN.SusinS. A.KroemerG. Mitochondrial membrane permeabilization during the apoptotic process. Ann N Y Acad Sci. 887 1830 1999
  97. 97. RenaultT. T.ManonS.BaxAddressed.tokill.Biochimie 2011 Sep;93 9 137991 .
  98. 98. MarzoI.BrennerC.ZamzamiN.JurgensmeierJ. M.SusinS. A.VieiraH. al. Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science. 1998Se Sep 25;281 5385 202731 .
  99. 99. ASBelzacqVieira. H. L.VerrierF.VandecasteeleG.CohenI.PrevostM. al. 2 and Bax modulate adenine nucleotide translocase activity. Cancer Res. 2003 Jan 15;63 2 5416 .
  100. 100. ZhivotovskyB.GalluzziL.KeppO.KroemerG.Adeninenucleotide.translocasea.componentof.thephylogenetically.conservedcell.deathmachinery. Cell Death Differ. 2009 Nov;16 11 141925 .
  101. 101. ShimizuS.TsujimotoY.ProapoptoticB. 3 Bcl-2 family members induce cytochrome c release, but not mitochondrial membrane potential loss, and do not directly modulate voltage-dependent anion channel activity. Proc Natl Acad Sci U S A. 2000 Jan 18;97 2 57782 .
  102. 102. PastorinoJ. G.TafaniM.RothmanR. J.MarcinkeviciuteA.HoekJ. B.FarberJ. L. Functional consequences of the sustained or transient activation by Bax of the mitochondrial permeability transition pore. J Biol Chem. 1999Oc Oct 29;274 44 317349 .
  103. 103. al. 2 prevents apoptotic mitochondrial dysfunction by regulating proton flux. Proc Natl Acad Sci U S A. 1998 Feb 17;95 4 14559 .
  104. 104. PastorinoJ. G.ChenS. T.TafaniM.SnyderJ. W.FarberJ. L. The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition. J Biol Chem. 1998Ma Mar 27;273 13 77705 .
  105. 105. BoyaP.MoralesM. C.Gonzalez-PoloR. A.AndreauK.GourdierI.PerfettiniJ. al. The chemopreventive agent N-(4-hydroxyphenyl)retinamide induces apoptosis through a mitochondrial pathway regulated by proteins from the 2 family. Oncogene. 2003 Sep 18;22 40 622030 .
  106. 106. KandasamyK.SrinivasulaS. M.AlnemriE. S.ThompsonC. B.KorsmeyerS. J.BryantJ. al. Involvement of proapoptotic molecules Bax and Bak in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced mitochondrial disruption and apoptosis: differential regulation of cytochrome c and Smac/DIABLO release. Cancer Res. 2003Ap Apr 1;63 7 171221 .
  107. 107. RavagnanL.MarzoI.CostantiniP.SusinS. A.ZamzamiN.PetitP. al. Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore. Oncogene. 1999Ap Apr 22;18 16 253746 .
  108. 108. ZhangL.YuJ.ParkB. H.KinzlerK. W.VogelsteinB.Roleof. B. A. X.inthe.apoptoticresponse.toanticancer.agents Science. 2000No Nov 3;290 5493 98992 .
  109. 109. RaisovaM.HossiniA. al.TheBax.Bclratiodetermines.thesusceptibility.ofhuman.melanomacells.toC.D9Fas-mediatedapoptosis. J, Riebeling C, Wieder T, Sturm I, et al. The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis. J Invest Dermatol. 2001 Aug;117 2 33340 .
  110. 110. Perez-NavarroE.GavaldaN.GratacosE.AlberchJ. Bra2-derived neurotrophic factor prevents changes in Bcl-2 family members and caspase-3 activation induced by excitotoxicity in the striatum. J Neurochem. 2005 Feb;92 3 67891 .
  111. 111. Guan QH, Pei DS, Xu TL, Zhang GY. Brain ischemia/reperfusion-induced expression 5 DP5 and its interaction with Bcl-2, thus freeing Bax from Bcl-2/Bax dimmers are mediated by c-Jun N-terminal kinase (JNK) pathway. Neurosci Lett. 2006 Jan 30;393(2-3):226-30.
  112. 112. DengX.KornblauS. M.RuvoloP. P.MayW. S.Jr Regulation 2 Bcl2 phosphorylation and potential significance for leukemic cell chemoresistance. J Natl Cancer Inst Monogr. 2001 28 307 .
  113. 113. 2010Yehuda-ShnaidmanE.KalderonB.AzazmehN.Bar-TanaJ. Gating of the mitochondrial permeability transition pore by thyroid hormone. FASEB J. 2010 Jan;24 1 93104 .
  114. 114. RuvoloP. P.DengX.MayW. S.Phosphorylation 2 Bcl2 and regulation of apoptosis. Leukemia. 2001 Apr;15 4 51522 .
  115. 115. ShibasakiF.KondoE.AkagiT.Mc KeonF. Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and 2 Nature. 1997 Apr 17;386 6626 72831 .
  116. 116. ErinN.BronsonS. K.BillingsleyM. L. Calcium-dependent interaction of calcineurin with 2 in neuronal tissue. Neuroscience. 2003;117 3 54155 .
  117. 117. D’ArezzoS.IncerpiS.DavisF. Rapid nongenomic effects 6 3,5,3’-triiodo-L-thyronine on the intracellular pH of L-6 myoblasts are mediated by intracellular calcium mobilization and kinase pathways. Endocrinology. 2004 Dec;145 12 5694703 .
  118. 118. al. Thyroid hormone activates adenosine 5’-monophosphate-activated protein kinase via intracellular calcium mobilization and activation of calcium/calmodulin-dependent protein kinase kinase-beta. Mol Endocrinol. 2008 Apr;22 4 893903 .
  119. 119. GorlachA.KlappaP.KietzmannT.Theendoplasmic.reticulumfolding.calciumhomeostasis.signalingredoxcontrol.AntioxidRedox.Signal 2006 Sep-Oct;8(9-10):1391-418.
  120. 120. PattersonR. L.BoehningD.SnyderS. H. Inositol 1 4 5 -trisphosphate receptors as signal integrators. Annu Rev Biochem. 2004
  121. 121. Joseph SK, Hajnoczky 3 IP3 receptors in cell survival and apoptosis: Ca2+ release and beyond. Apoptosis. 2007 May;12 5 95168 .
  122. 122. AssefaZ.BultynckG.SzlufcikK.NadifKasri. al. Caspase-3-induced truncation of type 1 inositol trisphosphate receptor accelerates apoptotic cell death and induces inositol trisphosphate-independent calcium release during apoptosis. J Biol Chem. 2004Oc Oct 8;279 41 4322736 .
  123. 123. VerbertL.LeeB.KocksS. L.AssefaZ.ParysJ. al.Caspase-3-truncatedtype. .inositol1,4,5-trisphosphate.receptorenhances.intracellular 2 leak and disturbs Ca2+ signalling. Biol Cell. 2008 Jan;100 1 3949 .
  124. 124. Wojcikiewicz RJ, Oberdorf JA. Degradation of inositol 1,4,5-trisphosphate receptors during cell stimulation is a specific process mediated by cysteine protease activity. J Biol Chem. 1996Ju Jul 12;271 28 166525 .
  125. 125. al. The regulatory domain of the inositol 1 4 5 -trisphosphate receptor is necessary to keep the channel domain closed: possible physiological significance of specific cleavage by caspase 3. Biochem 2004 2004 Jan 15;377(Pt 2):299-307.
  126. 126. SzlufcikK.MissiaenL.ParysJ. B.CallewaertG.De SmedtH.UncoupledI. P.receptorcan.asfunctiona.Ca2+-leakchannel.cellbiological.pathologicalconsequences. Biol Cell. 2006 Jan;98 1 114 .
  127. 127. JayaramanT.MarksA. R. Calcineurin is downstream of the inositol 1,4,5-trisphosphate receptor in the apoptotic and cell growth pathways. J Biol Chem. 2000Ma Mar 3;275 9 641720 .
  128. 128. Bray GA. Use and abuse of appetite-suppressant drugs in the treatment of obesity. Ann Intern Med. 1993Oc Oct 1;119(7 Pt 2):707-13.
  129. 129. ParascandolaJ.Dinitrophenolbioenergeticsan.historicalperspective.MolCell.Biochem 1974No Nov 15;5(1-2):69-77.
  130. 130. JDBaxterWebb. P.Thyroidhormone.mimeticspotential.applicationsin.atherosclerosisobesity.type.diabetes Nat Rev Drug Discov. 2009 Apr;8 4 30820 .
  131. 131. TancevskiI.RudlingM.EllerP.Thyromimeticsa.journeyfrom.benchto.bed-side Pharmacol Ther. 2011 Jul;131 1 339 .
  132. 132. WojtczakL.WieckowskiM. R.SchonfeldP. Protonophoric activity of fatty acid analogs and derivatives in the inner mitochondrial membrane: a further argument for the fatty acid cycling model. Arch Biochem Biophys. 1998Se Sep 1;357 1 7684 .
  133. 133. BernardiP.PenzoD.WojtczakL. Mitochondrial energy dissipation by fatty acids. Mechanisms and implications for cell death. Vitam Horm. 65 97126 2002
  134. 134. al. Synthesis and hypolipidemic and antidiabetogenic activities of beta,beta,beta’,beta’-tetrasubstituted, long-chain dioic acids. J Med Chem. 1989 Sep;32 9 207284 .
  135. 135. KalderonB.SheenaV.ShachrurS.HertzR.Bar-TanaJ. Modulation by nutrients and drugs of liver acyl-CoAs analyzed by mass spectrometry. J Lipid Res. 2002 Jul;43 7 112532 .
  136. 136. KalderonB.HertzR.Bar-TanaJ. Tissue selective modulation of redox and phosphate potentials by beta,beta’-methyl-substituted hexadecanedioic acid. Endocrinology. 1992 Oct;131 4 162935 .
  137. 137. RussellJ. C.ShillabeerG.Bar-TanaJ.LauD. C.RichardsonM.WenzelL. al. Development of insulin resistance in the JCR:LA-cp rat: role of triacylglycerols and effects of MEDICA 16. Diabetes. 1998 May;47 5 7708 .
  138. 138. MayorekN.KalderonB.ItachE.Bar-TanaJ. Sensitization to insulin induced by beta,beta’-methyl-substituted hexadecanedioic acid (MEDICA 16 in obese Zucker rats in vivo. Diabetes. 1997 Dec;46 12 195864 .
  139. 139. SobollS. Thyroid hormone action on mitochondrial energy transfer. Biochim Biophys Acta. 1993Au Aug 16;1144 1 116 .
  140. 140. BobylevaV.PazienzaT. al. Decrease in mitochondrial energy coupling by thyroid hormones: a physiological effect rather than a pathological hyperthyroidism consequence. FEBS Lett. 1998Ju Jul 3;430 3 40913 .
  141. 141. SamovskiD.KalderonB.Yehuda-ShnaidmanE.Bar-TanaJ. Gating of the mitochondrial permeability transition pore by long chain fatty acyl analogs in vivo. J Biol Chem. 2010Ma Mar 5;285 10 687990 .
  142. 142. YangE.ZhaJ.JockelJ.BoiseL. H.ThompsonC. B.KorsmeyerS. J.Bada.heterodimericpartner.for-XBcl.L. 2 displaces Bax and promotes cell death. Cell. 1995 Jan 27;80 2 28591 .
  143. 143. ZhaJ.HaradaH.YangE.JockelJ.KorsmeyerS. J. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 1433 not BCL-X(L). Cell. 1996 Nov 15;87 4 61928 .

Written By

Einav Yehuda-Shnaidman, Bella Kalderon and Jacob Bar-Tana

Submitted: April 12th, 2012 Published: July 18th, 2012