Scholarly article on 4-Nitrophenylacetic acid 104-03-0 from Journal of the American Chemical Society p. 1199,1201, 1203

J. Endocrinol. Invest. 24: 897-913, 2001

REVIEW ARTICLE

Control of energy metabolism by iodothyronines

A. Lanni*, M. Moreno**, A. Lombardi***, P. de Lange*, and F. Goglia**

*Department of Life Sciences, Second University of Naples, Caserta; **Faculty of Science, University

del Sannio, Benevento; ***Department of General and Environmental Physiology, “Federico II”

University, Naples, Italy

ABSTRACT. One of the most widely recognized ef-

fects of thyroid hormones (TH) in adult mammals is

their influence over energy metabolism. In the past,

this has received much attention but, possibly be-

cause of the complex mode of action of thyroid

hormones, no universally accepted mechanism to

explain this effect has been put forward so far.

Significant advances in our understanding of the

biochemical processes involved in the actions of TH

have been made in the last three decades and now

it seems clear that TH can act through both nucle-

ar-mediated and extranuclear-mediated pathways.

TH increase energy expenditure, partly by reduc-

ing metabolic efficiency, with control of specific

genes at the transcriptional level, being is thought

to be the major molecular mechanism. However,

both the number and the identity of the thyroid-

hormone-controlled genes remain unknown, as do

their relative contributions. The recent discovery of

uncoupling proteins (UCPs) (in addition to UCP1 in

brown adipose tissue) in almost all tissues in ani-

mals, including humans, has opened new perspec-

tives on the understanding of the mechanisms in-

volved in the regulation of energy metabolism by

thyroid hormones. Other approaches have includ-

ed the various attempts made to attribute changes

in respiratory activity to a direct influence of thy-

roid hormones over the mitochondrial energy-trans-

duction apparatus. In addition, an increasing num-

ber of studies has revealed that TH active in the

regulation of energy metabolism include not only

T₃, but also other iodothyronines present in the bi-

ological fluids, such as 3,5-diiodothyronine (3,5-T₂).

This, in turn, may make it possible to explain some

of the effects exerted by TH on energy metabolism

that cannot easily be attributed to T₃.

(J. Endocrinol. Invest. 24: 897-913, 2001)

INTRODUCTION

hormones, and of serum levels, but also of the in-

tracellular transformations of these hormones with-

in different tissues (3). In fact, the peripheral avail-

ability of iodothyronines depends mostly on local

deiodination of T₄and T₃and, consequently, on the

activity of deiodinase enzymes. For that reason,

deiodination activity is crucial to the local home-

ostasis of thyroid hormones (TH).

TH play an important role in several physiological

processes, such as differentiation, growth, cogni-

tive development and metabolism. One of the most

widely recognized effects of TH in adult mammals

is the regulation of energy metabolism (4). Despite

there being a substantial literature on this topic, the

mechanisms by which TH actually regulate energy

metabolism are still far from clear. The control of

energy metabolism requires the involvement of a

multitude of biochemical and molecular mecha-

nisms that may involve the participation of several

cellular compartments. Indeed, both nuclear-me-

The thyroid gland produces two main hormones: T₄

and T₃, T₄being the major one since, under normal

conditions, only a small amount of T₃is secreted by

this gland. However, T₄is converted to T₃, its bio-

logically more active metabolite, by the tissue-spe-

cific deiodinase enzymes widely distributed in the

periphery. This process accounts for about 80% of

daily T₃production, the remainder being secreted

by the thyroid (1, 2). Strictly speaking, evaluation of

the thyroid status of an individual requires knowl-

edge not only of the thyroidal production of the

Key-words: Thyroid hormone, 3,5-diiodothyronine, mitochondrion, re-

ceptor; uncoupling protein, proton-leak, redox-slip, energy metabolism.

Correspondence: Prof. Fernando Goglia, Facoltà di Scienze, Università

degli Studi del Sannio, Via Port’Arsa 11, 82100 Benevento, Italy.

E-mail: goglia@unisannio.it

Accepted April 27, 2001

897

Iodothyronines and energy metabolism

diated and extranuclear-mediated actions may un-

derlie the control exerted by TH on energy meta-

bolism. The nuclear-mediated pathway involves a

control of gene transcription mediated by several

T₃-binding transcription factors belonging to the

nuclear receptor superfamily. Various aspects of the

molecular mechanisms involved in this pathway

have recently been discussed in two excellent re-

views (5, 6), so they will not be further discussed in

this article. In actual fact, the nuclear-mediated sig-

naling pathway is universally accepted, while the

extranuclear-mediated pathway is still very much a

matter of debate.

The first line of evidence for a nuclear-mediated ef-

fect of T₃on energy metabolism came from the

studies performed by Tata et al. in the 1960s (7, 8).

These Authors showed that administration of T₃to

hypothyroid rats induces an increase in their basal

metabolic rate, while the simultaneous injection of

T₃in combination with actinomycin D completely

abolishes the stimulatory effect of T₃, pointing to-

wards the involvement of transcription. However,

both the number and the identity of the thyroid-

hormone-controlled genes remain unknown, as do

their relative contributions. On the other hand,

some other characteristics of the effects of T₃on

energy metabolism have been described. These ef-

fects have been shown to be: 1) independent of

thyroid-hormone nuclear receptors; 2) independent

of protein synthesis; and 3) evident in the short-

term. These characteristics emphasize that, in ad-

dition to nuclear-mediated actions, thyroid hor-

mones can stimulate cellular activities through in-

teractions with extranuclear components (9).

Mitochondria are considered to be likely subcellular

targets for thyroid hormones because of their cen-

tral role in cellular energy-transduction (10, 11). In

fact, both the activity and the number of these or-

ganelles are influenced by the thyroid state of the

animal. In addition, T₃plays an important role in the

regulation of mitochondrial function in several meta-

bolically very active tissues, such as skeletal muscle,

heart, kidney and liver (10). Mitochondria extracted

from the tissues of hyperthyroid rats display respira-

tion rates substantially greater than those recorded

for euthyroid controls, whereas mitochondria from

hypothyroid animals have lower respiration rates. The

effects of TH are often divided into: 1) short-term ef-

fects, occurring within minutes or a few hours; and

2) long-term effects, occurring over several hours or

days. This being so, it is quite conceivable that both

nuclear-mediated and extranuclear-mediated path-

ways are in operation at the cellular level mediating

the effects exerted by TH on energy metabolism.

The purpose of this review is: 1) to discuss these ef-

fects of TH in the broader context of the regulation

of energy metabolism; and 2) to describe the vari-

ous mechanisms by which TH may control energy

metabolism.

MECHANISMS UNDERLYING THE CONTROL

OF THE ENERGY METABOLISM BY

THYROID HORMONES

In general terms, the cellular processes that have

been proposed as candidates to explain the effects

of TH on energy metabolism can be categorized as

processes acting on: 1) the maintenance of trans-

membrane ionic gradients; 2) substrate cycles; 3)

the glycerol-3-phosphate/NADH shuttle; or 4) the

mitochondrial energy-transduction apparatus. The

first three of these categories have been discussed

in a number of recent reviews (10-13) and will be

dealt with only briefly in this article, so d) will con-

stitute the main part of this review.

Maintenance of transmembrane ionic gradients

As far as these ionic gradients are concerned, two

mechanisms, the Na⁺and K⁺gradients across the

cell membrane and the Ca⁺⁺gradients inside the

cell, have received the bulk of the attention.

Na⁺/K⁺ATPase

TH increases Na⁺/K⁺ATPase activity and it has been

hypothesized that this effect might account for an im-

portant fraction of the thermogenic effect of TH (14).

Some Authors, however, estimated that this mecha-

nism could account for only a small fraction of the

overall thermogenic effect of TH (15-17). In order to

establish the contribution made by the Na⁺/K⁺-pump

to thyroid thermogenesis, experiments have been

carried out in Na⁺-free media (to block the pump).

These conditions, however, can also affect other

mechanisms, such as the Na⁺-H⁺and Na⁺-Ca⁺⁺anti-

ports, and together these mechanisms could repre-

sent both a substantial part of the energy expendi-

ture attributed to Na⁺/K⁺ATPase (18) and a pathway

for the action of T₃. Indeed, it has recently been

shown that T₃is able to stimulate the Na⁺/H⁺antiport

in L6 muscle cells (19). The primary event in the TH-

induced activation of Na⁺/K⁺ATPase may be a re-

duction in the Na⁺and K⁺gradients, with activation

of the Na⁺/K⁺-pump as a secondary effect. Some

studies, however, seem to suggest that T₃may di-

rectly influence the pump by increasing the expres-

sion of Na⁺/K⁺ATPase.

Calcium

Ca⁺⁺plays an important role in the regulation of a

wide variety of cellular processes. While the extra-

898

A. Lanni, M. Moreno, A. Lombardi, et al.

cellular Ca⁺⁺concentration is in the mM range, the

cytosolic concentration is kept much lower and

within a narrow range (10^-7-10^-8M), and even min-

imal changes may have large effects on the meta-

bolic processes within the cell, such as mitochon-

drial metabolism (20). The maintenance of the Ca⁺⁺

gradient is largely the function of Ca⁺⁺-dependent

ATPases in the cell membrane and in the endo-

plasmic or sarcoplasmic reticulum (SR) (18). It has

been estimated that about 10% of the cell energy

expenditure is needed simply for cytosolic Ca⁺⁺

homeostasis, although it depends on the cell type

and the prevailing physiological conditions. Most

of the published studies on the effects of TH on in-

tracellular Ca⁺⁺cycling and energy expenditure

have been performed on skeletal muscle (17). TH

can apparently influence Ca⁺⁺turnover by produc-

ing increases in both the volume of the SR and the

density of Ca⁺⁺-pumps in the SR, via the regulation

of the expression of the corresponding genes. In

addition, TH can directly stimulate plasma-mem-

brane Ca⁺⁺-ATPase activity in a way that does not

rely on an upregulation of gene expression (9, 21).

lates α-GPDm could involve stimulation of the tran-

scription of the corresponding gene (25). The in-

creased α-GPDm activity leads to a faster rate of glu-

coneogenesis from glycerol and may contribute to

increased thermogenesis since only two ATPs/oxi-

dised molecules will be formed in this way. However,

the real contribution of this shuttle to the thermo-

genic effect of TH has not been directly assessed.

EFFECTS OF TH ON MITOCHONDRIAL

ENERGY-TRANSDUCTION APPARATUS

As cited in the Introduction, because of the central

role known to be played by mitochondria in cellu-

lar energy-transduction, several reports concerning

the effect of TH on mitochondrial activity can be

found in the literature.

Mitochondria are the site of oxidative phosphoryla-

tion, a step-by-step process responsible for most ATP

synthesis within the cells. Oxidative phosphorylation

consists of mitochondrial ATP synthesis from ADP,

which is driven by the electron flow from the reduced

substrates (NADH and FADH) to oxygen. Mitchell

proposed that the oxidation of the reduced substrate

that takes place via the respiratory chain may be cou-

pled to a pumping of protons from the mitochondri-

al matrix, thus generating an electrochemical proton

gradient (ꢀμH⁺) across the inner membrane. ꢀμH⁺

provides the force driving the protons back to the

matrix through ATP synthase, which couples proton

transport across the membrane to the phosphoryla-

tion of ADP (Fig. 1A). As ATP synthesis is not perfectly

compled to oxygen consumption, the system is not

completely efficient, a leakage of protons across the

mitochondrial membrane directly dissipating part of

the proton electrochemical gradient as heat. An ad-

ditional phenomenon that reduces the efficiency of

oxidative phosphorylation is a failure of the proton

pumps in the respiratory chain, called “redox-slip”.

The above two phenomena, which are responsible

for a reduced oxidative phosphorylation efficiency,

are represented schematically in Figure 1B.

Substrate cycling

TH influence the intermediary metabolism of car-

bohydrates, lipids and proteins. In essence, the

mechanism underlying induced changes in sub-

strate cycling are essentially the same as those un-

derlying effects on ion cycling: an acceleration of a

pathway (metabolic or ionic) by external stimuli to

maintain a basically constant steady-state, consist-

ing a “futile cycle“. As to substrates, this involves an

acceleration of their turnover without a change in

their steady-state level. The contribution made by

a given substrate cycle to the thermogenic effect

of TH seems to be low (13), and among the other

cycles protein turnover seems to involve a negligi-

ble energy cost (22). The substrate cycle that has

therefore received most attention is “lipogenesis-

lipolysis”. TH, in fact, stimulate both lipogenesis

and lipolysis (23).

The effects of TH on mitochondrial activity are all, in

one way or another, related to the effects that they

exert on cellular respiration (calorigenic effect). The

first hypothesis concerning the mechanism underlying

the calorigenic effect of TH dates back to the early

1950s, when Martius et al. (26) and Lardy et al. (27)

found that the addition of T₄to isolated mitochon-

dria in vitro led to a decrease in the efficiency of mi-

tochondrial respiration. They hypothesised that the

major cellular mechanism underlying the calorigenic

effect of TH is an “uncoupling of oxidative phospho-

rylation”, measured as a reduced respiratory control

ratio (RCR). The value of this parameter is obtained

Glycerol-3-phosphate/NADH shuttle

The NADH shuttle, with the associated cytosolic

NAD-linked glycerol-3-phosphate dehydrogenase (α-

GPDc) and FAD-linked mitochondrial α-glyceropho-

sphate dehydrogenase (α-GPDm), has received con-

siderable attention as a possible biochemical mech-

anism involved in TH-induced thermogenesis. More

than 35 years ago, Lee et al. (24) demonstrated that

TH stimulate α-GPDm activity in metabolically rele-

vant tissues and that the increases correlate well with

the increases in O₂consumption. Recently, it has

been shown that the mechanism by which T₃stimu-

899

Iodothyronines and energy metabolism

from the ratio of two mitochondrial respiration states:

that in which the synthesis of ATP is at maximal rate

(State 3), and that in which ATP synthesis is either ab-

sent or extremely low (State 4). This hypothesis was

subsequently discarded and regarded as not physio-

logically relevant since a large concentration of T₄

and T₃was required and, moreover, because the ef-

fects seen in vitro could not be demonstrated in vivo.

Actually, most papers have reported that mitochon-

dria in different thyroid states show no differences in

RCR values. This absence of a change in RCR, how-

ever, does not exclude the possibility that changes

in State 3 and/or State 4 may occur. In fact, a con-

comitant increase in (i) proton-leak kinetic, which is

mostly responsible for State 4 respiration, and (ii) the

phosphorylating-machinery kinetics (ATP synthase,

adenine-nucleotide translocator, phosphate trans-

porter), which are responsible for State 3 respiration,

can lead to an unchanged set-point for the coupling

ratio without excluding the possibility that an uncou-

pling ratio may take place (28). Moreover, the inter-

pretation of these results obtained in vitro on isolat-

ed mitochondria is complicated because in vivo res-

piratory control is between States 3 and 4, and may

change depending on the metabolic state of the cell.

In addition, the proton-leak and the phosphorylating

machinery compete for the same driving force, and

the question arises as to whether the contribution of

proton-leak to the metabolic rate remains significant

at higher rates of metabolism, when the H⁺flux

through ATP synthase must increase. It has recently

been shown that the proton-leak remains an impor-

tant component of the rat’s metabolic rate even at

higher metabolic rates. The published data suggest

that the proton-leak accounts for about 20% of rat

standard metabolic rate (SMR), making the proton-

leak the largest individual contributor to the SMR (29).

The questions as to whether thyroid-hormone-in-

duced uncoupling is: 1) a physiological phenomenon;

2) a non-physiological response seen only with high

levels of the hormones; or 3) an in vitro artifact have

continued for almost half a century. However, when

compared to those from euthyroid animals, mito-

chondria isolated from hypothyroid animals display

lower State 4 and State 3 respiratory rates, while mi-

tochondria from hyperthyroid rats show higher val-

ues. The mitochondrial proton-motive force, on the

other hand, decreases in the order hypothyroid > eu-

thyroid > hyperthyroid (30).

by a regulation of the expression of nuclear-encoded

as well as mitochondrially-encoded respiratory genes

(25), since the mitochondrion is a unique cellular or-

ganelle containing a distinct and separate genome.

We have already discussed some aspects of the ex-

pression of nuclear-encoded and mitochondrially-en-

coded respiratory genes in a recent review (11).

A variety of experimental approaches have been

used to analyze the mechanisms underlying TH-de-

pendent alterations in mitochondrial function. In par-

ticular, in order to examine the extent to which the

components of the respiratory chain limit respira-

tion, metabolic control analysis has been used. This

technique permits to determine the proportional

control that individual steps in a complex pathway

exert on the flux through that pathway (31). Groen

et al. (32) first applied this approach to oxidative

phosphorylation and, in recent years, Harper et al.

(33) have refined and adapted it to examine how

the thyroid state influences the control exerted on

mitochondrial respiration by individual steps. These

latter Authors introduced top-down elasticity analy-

sis as an approach to identify blocks of reactions

that have a changed kinetic response (i.e. changed

elasticity) to a common intermediate as the sites of

effector action which are significant in changing the

flux through the intermediate (33, 34).

In this approach, oxidative phosphorylation can be

considered a system consisting of a few compo-

nents or blocks of reactions. These are: 1) the re-

actions that are involved in the oxidation of sub-

strates and that generate ꢀμH⁺: substrate translo-

case, substrate dehydrogenase and the compo-

nents of the electron transport chain (Fig. 1A); 2)

the overall reactions that dissipate ꢀμH⁺for the

synthesis and export of ATP: ATP synthase, the

phosphate transporter and the adenine nucleotide

translocator (AdNT) (Fig. 1A); and 3) the reactions

that dissipate ꢀμH⁺without ATP synthesis, repre-

sented by the cation cycles and the leak of protons

across the inner membrane, which together are

called the “proton leak” (Fig. 1B).

The components described above control both

the respiration associated with ATP synthesis and

that not associated with ATP synthesis in differ-

ent ways, which implies that a change in the ac-

tivity of a single block will have different effects

on States 4 and 3. Actually, State 4 is controlled

principally by the leak of protons across the mito-

chondrial inner membrane (responsible principal-

ly for mitochondrial uncoupling) and to a lesser

extent by the activity of the respiratory chain. On

the other hand, the control over State 3 is exerted

via changes in both the activity of the respiratory

chain and that of the phosphorylating system (i.e.

Effects of TH on State 3 and State 4

mitochondrial respiration

TH affect mitochondrial oxygen consumption by in-

fluencing both State 3 and State 4 respiration. Each

of these influences may be mediated, at least in part,

900

A. Lanni, M. Moreno, A. Lombardi, et al.

ꢀµH⁺

generators are unchanged in liver mitochondria

from hypothyroid animals, while the kinetics of the

ꢀμH⁺consumers are altered. This supports the idea

that the important effects of TH on State 3 are ac-

tually exerted on ATP synthase or AdNT. Indeed,

AdNT activity is affected by the thyroid state (36)

and the injection of T₃into hypothyroid rats induces

a two-fold increase in the mitochondrial AdNT con-

tent and a three-fold increase in its activity (37). The

notion that a higher AdNT activity is responsible for

the increase in State 3 respiration also fits well the

data of Seitz et al. (38) who showed that the cy-

tosolic and mitochondrial ADP/ATP ratios are af-

fected by thyroid state.

A

H⁺

ATP ADP

AdNT

ATPase

Respiratory chain

Sred Sox

1/20 H₂O

ADP

ATP

H⁺

When the same analysis, however, was employed to

investigate the effect of hyperthyroidism on State 3

respiration, no significant change in the kinetics of

the ꢀμH⁺consumers was detected, although a sig-

nificant change in the kinetics of the ꢀμH⁺produc-

ers was reported (39). Thus, these findings do not

seem to match with the previous conclusions, al-

though they do seem to suggest that different me-

chanisms may be operative in the hypothyroid and

hyperthyroid states. In addition, the increased flow

through the respiratory chain elicited by T₃can be

accomplished either by increasing the amounts of the

components of the respiratory chain or by increasing

their reduction state (40). Furthermore, since hyper-

thyroid mitochondria have a higher Ca⁺⁺content than

euthyroid ones, State 3 respiration could be increased

by T₃via a rise in mitochondrial calcium uptake, which

in turn may induce an increase in mitochondrial de-

hydrogenase activity (41). In State 4, the mitochon-

drial respiration rate is largely controlled by the pro-

ton-leak across the inner mitochondrial membrane,

and TH could conceivably act predominantly by al-

tering this leak (which indeed is depressed in hy-

pothyroid mitochondria and stimulated in hyper-

thyroid mitochondria) (42-44).

ꢀµH⁺

B

H⁺

Respiratory chain

e-

UCP

Sred Sox 1/20 H₂O

H⁺

Redox slip

Proton leak

Fig. 1 - Schematic representation of mechanisms linking respira-

tion to ATP synthesis (A) and of mechanisms underlying reduced

mitochondrial efficiency (B). Only the inner mitochondrial mem-

brane is depicted. The bold black line represents the lipid bilayer.

The respiratory chain works as a H⁺pump, generating an electro-

chemical proton gradient (ꢀμH⁺). ꢀμH⁺is used by ATPase to phos-

phorylate ADP. ATP and ADP are then exchanged by AdNT (de-

picted in A). Alternatively, H⁺can enter the mitochondrial matrix by

mechanisms not coupled to ATP synthesis: i.e. by leaking across the

lipid bilayer or by protein-mediated H⁺transport (UCP, depicted in

B). This mechanism decreases ꢀμH⁺, activates respiration and in-

creases reoxidation and thermogenesis (uncoupled respiration).

Incomplete coupling of respiration can also be due to a redox slip

(depicted in B) in the respiratory chain: fewer protons are pumped

per oxygen consumed, causing reduced ꢀμH⁺production. In (B)

the dotted lines represent decreased proton pumping.

TH and mitochondrial efficiency

Many efforts have been made to elucidate the mole-

cular basis of the metabolic inefficiency induced by

TH in mitochondria. Two main mechanisms have

been proposed: 1) a classic uncoupler mechanism

based on the action of TH at the level of the proton-

leak; and 2) a slipping mechanism with more local-

ized effects at the level of the redox proton pumps.

A “slipping” of the respiratory chain can be defined

as a failure of the proton pumps, a situation in which

they transfer electrons with a reduced extrusion of

protons out across the membrane; this implies that a

higher respiratory rate, is necessary for a given level

of ATP synthesis (45-47) (Fig. 1B).

all the reactions involved in the synthesis and the

export of ATP) (34).

Hafner et al. (35), by using top-down elasticity anal-

ysis, showed that, by comparison with the situation

in the euthyroid controls, the kinetics of the ꢀμH⁺

TH and redox-slip

901

Iodothyronines and energy metabolism

About 20 years ago, the concept of the redox-slip

was a new unveiled uncoupling mechanism, and

since then it has been shown to be partially re-

sponsible for the basal respiration in mitochondria

(42, 46, 47). Moreover, just such a type of uncou-

pling has been proposed as an explanation for

stimulatory effects exerted by TH on respiration.

Brand et al. (42) concluded that the action of TH

is not primarily concerned with the quantity of res-

piratory chain components or of mitochondria but,

rather, with the leak/slip characteristics of mito-

chondria. Subsequently, however, Hafner et al. (48)

rejected the existence of slip and its role in medi-

ating hormonal effects. Schmehl et al. (49), on the

other hand, demonstrated the occurrence of the

slip reaction mainly at the level of the cytochrome

oxidase complex, although Brand et al. (50) re-

ported that no permanent functional alteration in

the constitutive oxidase was induced by hyperthy-

roidism (by comparison with the situation in eu-

thyroid mitochondria), indicating that the hormon-

al effects do not involve an inherent change in the

properties of the enzyme. However, the c-oxidase

(COX) complex has a very dynamic structure and,

during the isolation procedure and the reconstitu-

tion of the enzymes, some changes (i.e. confor-

mational, phosphorylation-dephosphorylation) can

take place. It is also known that changes in the lipid

environment, surface charge or pH alter the kinet-

ics of the complex. It has been postulated that, in

vivo, cytochrome c oxidase (and possibly other en-

zyme complexes of the respiratory chain) are in a

steady state between the phosphorylated and de-

phosphorylated forms (51, 52). The dephosphory-

lated enzyme is no longer controlled by the in-

tramitochondrial ATP/ADP ratio: it is controlled by

the ꢀμH⁺, and it shows an increased activity in the

presence of a high ATP/ADP ratio, thus leading to

an increased ꢀμH⁺. An increased ꢀμH⁺, conse-

quently, would decrease the efficiency of the com-

plex causing a slip of proton-pumping in cytochro-

me c oxidase (i.e. decreased H⁺/e^–stoichiometry).

It has been reported that there is a specific and

tight association between cytochrome c oxidase

and cardiolipin, which is functionally important for

the maximal activity of this enzyme (53). TH induce

a change in the phospholipid composition of the

inner membrane and stimulates cardiolipin synthase

activity through a rise in the mitochondrial phos-

phatidylglycerol pool (54). The increased amount

of cardiolipin stimulates several mitochondrial car-

riers and enzyme activities (55). Removal of cardi-

olipin from isolated cytochrome oxidase enzyme

leads to a decrease of about 60-70% in the elec-

tron transport, indicating that a modification of the

immediate lipid environment of the protein causes

it to malfunction. Canton et al. (56) suggested that,

because of the marked temperature-dependence

of the proton-leak processes, different contributions

of redox-slip and proton-leak to basal respiration

may be observed depending on the temperature

at which mitochondria are incubated. The contri-

bution made by the proton-leak to the basal respi-

ration is reduced at low temperatures (25 C) and

this reduction is accompanied by a higher contri-

bution of redox-slip to resting respiration. At 37 C,

the actual physiological temperature, the proton-

leak makes the predominant contribution to basal

respiration. In order to show an effect of T₃on re-

dox-slip, Luvisetto et al. (57) performed experi-

ments at an incubation temperature of 25 C; at this

temperature they showed that hyperthyroidism is

able to increase both proton-leak and redox-slip.

However, as the same Authors did not perform the

same experiment at 37 C, it is not clear whether T₃

affects redox-slip only at non-physiologically low

temperatures.

TH and proton-leak

As cited above, the proton-leak is the major process

controlling mitochondrial oxygen consumption when

cellular ATP requirements are low, and the size of

this leak has been measured in mitochondria from

liver, brain, kidney and skeletal muscle (34). This non-

productive proton-conductance pathway is physio-

logically important: 1) because it accounts for a high

proportion of cellular metabolic rates [e.g. 25% and

52% of the resting respiration rates of isolated rat

hepatocytes and perfused rat skeletal muscles, re-

spectively (58)] and 2) because an increased mass-

specific metabolic rate related to thyroid-hormone

levels is linked to an increased mitochondrial pro-

ton-leak (42). The mechanism by which the proton-

leak occurs is unclear. Some evidence suggests that

the phospholipid composition of the inner mem-

brane is correlated with the proton-conductance of

the membrane (59). However, variation in the phos-

pholipidcomposition of mitochondrial-membrane

phospholipids reconstituted in liposomes does not

appear to account for the difference in proton-con-

ductance (60). In addition, experiments on liposomes

made from inner-membrane phospholipids suggest

that the proton-conductance of a protein-free mem-

brane would support only 5% of the total proton-

leak in the rat (61). Therefore, it is clear that other

factors, such as specific proteins in the inner mem-

brane, could be responsibile of most of the mito-

chondrial proton-leak (62).

With regard to liver mitochondria, several studies

have indicated that AdNT is a candidate able both

902

A. Lanni, M. Moreno, A. Lombardi, et al.

to uncouple oxidative phosphorylation and to in-

teract with fatty acids (FA). Skulachev et al. (63)

showed that AdNT mediates the uncoupling effect

of FA in mitochondria and proteoliposomes. In fact,

AdNT operates as a transmembrane carrier for FA

anions by facilitating the H⁺-conducting FA cycle:

protonated FA diffuse to the mitochondrial matrix

through the membrane while anions are elec-

trophoretically expelled in the opposite direction

via AdNT (63). As reported before, TH increase the

mitochondrial AdNT content in the liver two-fold

when administered to hypothyroid rats (36). Thus,

the thyroid-hormone-induced uncoupling seen in

the liver can be explained by a hormone-induced

increase in the AdNT concentration, entailing an el-

evation of mitochondrial proton-conductance me-

diated by FA. In tissues other than liver, in addition

to the effect on AdNT, the thyroid-hormone-in-

duced decrease in energy coupling may be due to

an induction of proteins belonging to the family of

uncoupling proteins (UCPs).

thors concluded that the molecular role of CoQ

probably resides in cooperation with FA (on the

basis that there is physical contact between these

two components at the membrane-UCP1 interface)

(71).

The presence of UCP1 in brown adipose tissue

(BAT) together with the finding of a high density of

nuclear T₃receptors in this tissue have, not surpris-

ingly, focused attention on a possible role for this

hormone in modifying the function of UCP1. In fact,

UCP1-gene transcription is stimulated by T₃, which

acts via its receptor on a discrete sequence of the

gene well upstream in the 5’ flanking region of the

gene (72). In addition, two thyroid response ele-

ments are delineated within this sequence, which

is separated from the sequence on which nore-

pinephrine (NE), via cAMP, stimulates gene- ex-

pression (73). A synergism between T₃and NE has

been demonstrated both in vivo and in vitro (73) as

well as in rat cultured brown adipocytes (74), and

it has been suggested that T₃plays a permissive

role in stimulating the BAT response to cold.

Moreover, it has been demonstrated that local pro-

duction of T₃by the deiodination of T₄via 5’D-II ac-

tivity is essential for the induction of UCP1-gene

transcription (75, 76). For this reason, conditions

that inhibit 5’D-II activity (e.g. T4 administration to

hypothyroid rats) will lead to a reduced local gen-

eration of T₃and a blunted response to BAT. Very

recent studies, however, have indicated that T₃

alone vigorously stimulates UCP1 expression under

conditions in which there is minimal interference

with the sympathetic nervous system (SNS), point-

ing to a role of T₃that is independent of NE (77).

Since 1997, several genes that encode proteins

closely related to the UCP1 found in brown adipose

tissue have been discovered (64, 78). To date, five

genes have been identified in mammals: for UCP1,

UCP2, UCP3, BMCP1 (brain mitochondrial carrier

protein 1) or UCP5 and UCP4 . The expression pat-

tern of these genes, based on mRNA detection, has

been evaluated in various papers and reviewed (64,

78, 79). Briefly, UCP3 mRNA is found in skeletal

muscle, in heart and also in brown adipose tissue.

BMCP1/UCP5 and UCP4 are predominantly ex-

pressed in brain, while UCP2 is more widely ex-

pressed. Based on the relatively high similarity be-

tween UCP2 and UCP3, on the one hand, and

UCP1 on the other, it was predicted that these new

UCP homologues would have uncoupling activity.

When expressed in yeast, murine UCP2 and UCP3

both lower the potential of the mitochondrial mem-

brane, raise the respiration rate and reduce sensi-

tivity to uncouplers (80). These results, although ob-

tained in a non-physiological system, are indicative

UCPS AND TH

An increase in the proton-conductance may be as-

sociated with the presence of UCPs. Uncoupling

protein-1 (UCP1) cloned in 1985, and called UCP

until 1997, is an inner-mitochondrial-membrane

protein expressed exclusively in the brown adipo-

cyte. It dissipates the mitochondrial protoin-gradi-

ent generated by the respiratory chain, producing

heat instead of ATP (64). Two major hypotheses

have been put forward to explain the mechanism

by which UCP1 exerts this effect: 1) according to

the proton-buffering model, introduced by Klin-

genberg (65), UCP1 conducts protons through a

hydrophilic pathway lined with FA head groups,

which buffer the protons as they move across the

membrane whereas; 2) according to the FA proto-

nophore model, introduced by Garlid (66), UCP1

does not conduct protons at all, but it is rather an

anion carrier able to transport FA anions. In each

case, there would be a net transport of H⁺, and

there are arguments for and against both models

(67, 68). The requirement for FA for the purposes

of UCP1-mediated H⁺transport is generally be-

lieved to be absolute, although it has been ques-

tioned recently (69). It has been suggested that the

activators of UCP1 are most likely not the FA them-

selves, but a FA metabolite (70). Echtay et al. (71)

inferred that coenzyme Q is an obligatory co-factor

for UCP function on the grounds that when CoQ10

was added to reconstituted UCP1 from inclusion

bodies, FA-dependent H⁺transport reached the

same rate as that seen with native UCP1. The au-

903

Iodothyronines and energy metabolism

of an uncoupling property of these proteins. More-

over, recent studies show that mice overexpress-

ing UCP3 are hyperphagic and lean, with a de-

creased mitochondrial efficiency (81), while mice

lacking UCP3 show a reduced mitochondrial pro-

ton-conductance (82, 83). Administration of T₃to

rodents has been reported to increase the expres-

sion of the mRNA for UCP2 and UCP3 in heart and

skeletal muscle (84-87). These results are very im-

portant and suggest a hypothetical molecular

mechanism by which T₃increases energy expendi-

ture partly by reducing metabolic efficiency. We

showed that the expression of UCP3 mRNA in

skeletal muscle increased strongly during the tran-

sition from hypothyroidism to hyperthyroidism, and

an evaluation of the proton-leak in skeletal muscle

mitochondria revealed that those from hyperthy-

roid rats display a greater proton-leak than those

from their euthyroid or hypothyroid counterparts

(87). Jucker et al. (88), who assayed mitochondrial

energy coupling in skeletal muscle in vivo by a non-

invasive method (NMR spectroscopy), confirmed

that injection of T₃into hypothyroid rats led to a

mitochondrial uncoupling in skeletal muscle.

In a study in our laboratory on rat skeletal muscle

mitochondria, clear-cut changes in proton-leak ki-

netics that accompanied the transition from hy-

pothyroidism to hyperthyroidism disappeared when

BSA was included in the incubation medium (87).

An interpretation of these results could be that the

difference in proton-leak between the hypo- and

hyperthyroid states is related to differences in the

endogenous content of free fatty acids (FFA), which

are known mitochondrial uncouplers. BSA chelates

FFA and therefore abolishes the effect. However,

FFA may be important cofactors for UCP3-uncou-

pling activity, and the results may also be explained

on the basis of the crucial need for the presence of

these putative cofactors. In fact, this hypothesis

seems to be confirmed by the recent findings of

Echtay et al. (89), who reported that FFA are im-

portant factors for the activation by CoQ of UCP2

and UCP3 expressed in E.coli. In skeletal muscle,

physiological states associated with enhanced fat

metabolism are correlated with increased UCP3 ex-

pression. Such situations include starvation (90), and

fed animals given Intralipid plus heparin, which rais-

es circulating FFA levels (91). As hyperthyroidism is

accompanied by high levels of FFA, the effect of

TH on the UCP3 level could be mediated, at least

in part, by FFA [which may directly regulate the

transcription of UCP3 mRNA by interacting with

transcriptional factors such as peroxisome-prolifer-

ator activated receptor (PPAR)]. The UCP3 gene, in

fact, contains response elements for both TH and

PPARs (92), and agonists of PPARs have been

shown to regulate the expression of both UCP2 and

UCP3 (93).

In a very recent study we obtained evidence that

UCP3 has the potential to be the molecular deter-

minant for the regulation of resting metabolic rate

by T3 (94).

TH CONTROL OF MITOCHONDRIAL

ENERGY METABOLISM: THE

MITOCHONDRIAL-DEPENDENT PATHWAY

As stated above, the question of a direct action of

TH on mitochondria has long been controversial,

even though a large amount of evidence has ac-

cumulated supporting the putative direct effects

of TH. For example, when T₃is injected into hy-

pothyroid rats the respiration rate of mitochondria

isolated only 20-30 min later is found to be raised,

and this activation is unaffected by the use of a

protein-synthesis inhibitor (95, 96). Oxygen con-

sumption in isolated hepatocytes is stimulated by

T3, independently of any effect on protein synthe-

sis (97, 98), and this increase persists in uncoupled

hepatocytes and subsequently isolated mitochon-

dria (98). Perfusion of liver with T₃increases respi-

ration within 30 min (99-102) and this stimulation

correlates with observed increases in the uptake

of Ca⁺⁺and amino acids from the perfusate (101,

103). Nevertheless, the most important finding

confirming a direct mitochondrial pathway would

be the identification of specific binding sites for T₃

in mitochondria. In fact, high-affinity binding sites

for T₃were identified in the mitochondrial inner

membrane as long ago as 1975 by Sterling et al.

(104).

Although two other groups then confirmed the ex-

istence of such sites, the site-characterizations giv-

en in these later reports differed from each other

as well as from that in the initial report (105, 106). In

a further study, adenine nucleotide translocase was

claimed to be the mitochondrial receptor for T₃

(107) but this has not been confirmed by other in-

vestigators (108). The conflicting results referred to

above and the lack of a chemical identity for these

sites raised some doubts about their physiological

relevance and indeed their very existence.

Quite recently, however, the existence of specific

mitochondrial binding sites for T₃has received

strong support from the work of Wrutniak et al.

(109) and Morel et al. (110). The latter group sho-

wed by quantitative electron-microscopic autora-

diography that after an injection of radio-labelled

T₃, specific binding sites were displayed by five cell

compartments, including mitochondria. Wrutniak

904

A. Lanni, M. Moreno, A. Lombardi, et al.

et al., using a photoaffinity-labelling technique,

identified two T₃-binding proteins in a rat liver mi-

tochondrial extract. One, of 43 kD (p43), was lo-

cated in the matrix and the other, of 28 kD (p28), in

the inner membrane. In fact, p43 binds to one of

the five sequences highly related to the TH-re-

sponse element in the D-loop region of the mito-

chondrial genome (the region containing the pro-

moter of the mitochondrial genome). These results

led to the hypothesis that p43 could function as a

T₃-dependent mitochondrial transcription factor.

The same group (109) later showed that p43 has an

affinity for T₃that is similar to that of the T₃nucle-

ar receptor, and that it is able to stimulate mito-

chondrial protein synthesis. Western blots and im-

munoprecipitation, using antibodies raised against

the T₃-binding domain of the T₃nuclear receptor

c-Erb A α1 protein, indicated that p43 is at least re-

lated to an isoform of the T₃nuclear receptor c-Erb

A α1 (109). Wrutniak et al. (109) also showed that

expression of the truncated form of the c-Erb A α1

nuclear receptor in CV1 cells was imported into mi-

tochondria and was associated with a stimulation

of mitochondrial activity. To examine more direct-

ly the ability of p43 to activate mitochondrial tran-

scription, Casas et al. (111) performed in organello

transcription experiments using isolated rat liver mi-

tochondria and p43 proteins synthesized in rabbit

reticulocyte lysate; they observed that p43 in-

creases the levels of both precursors. Taken to-

gether, these results indicate that p43 may be a po-

tent T₃-dependent transcription factor for the mi-

tochondrial genome and strongly support the ex-

istence of a direct regulation by T₃of mitochondri-

al gene expression. More recently, p43 has been

shown to be able to heterodimerise with a truncat-

ed form of the PPARγ nuclear receptor (mtPPAR)

found in the mitochondrial matrix (112). These re-

sults could help to clarify the mechanisms underly-

ing the thyromimetic properties of PPARs. Be that

as it may, the above data do at least seem to sup-

port the hypothesis that a direct mitochondrial

pathway is involved in the action of T₃.

Horst et al. (100), examining the rapid effects of

iodothyronines on the respiratory capacity of per-

fused livers isolated from hypothyroid rats, showed

that 3,5-T2, as well as T₃and T₄, was able to pro-

duce a rapid stimulation of oxygen consumption.

In the same study, the Authors showed that the ef-

fects elicited by T₃and T₄were completely abol-

ished by inhibiting the deiodinase activity of the liv-

er, while the effect elicited by 3,5-T₂was unaffect-

ed by this inhibition. These results stimulated oth-

er groups to focus more deeply on a putative phys-

iological role for 3,5-T₂.

Our group has shown that chronic administration of

3,5-T₂to hypothyroid rats significantly enhances

both the mitochondrial respiratory rate and cyto-

chrome COX activity (113, 114). When 3,5-T₂and

T₃were acutely injected, 3,5-T₂had an earlier ef-

fect on respiratory parameters than T₃, the effect of

the former being evident as soon as 1 h after its

injection, while that of the latter became evident

only after 24 h. Effects of 3,5-T₂on respiratory pa-

rameters have also been demonstrated by others,

in rats (115) and also in humans (116). O’Reilly et al.

(115) reported that the rapid effect of 3,5-T₂on mi-

tochondrial respiration was independent of chan-

ges in protein synthesis (since it was also evident in

the presence of cycloheximide). Interestingly, the

direct effects of 3,5-T₂on the mitochondrial meta-

bolism have recently been confirmed in mito-

chondria isolated from the liver and red muscle of

the goldfish (117), thus indicating that the influ-

ence of 3,5-T₂is not restricted to mammals.

The hypothesis that 3,5-T₂has the mitochondrion

as its direct target is supported by our identifica-

tion of specific binding sites for 3,5-T₂at the mito-

chondrial level (118). The data, however, should be

treated with some caution because of a limitation

inherent in these studies: namely, that [3,5-¹²⁵I]T₂

was used at low specific activity (due to the inner-

ring labeling procedure). Because of this, it was

possible to perform binding studies only over a nar-

row range of concentrations and thus there may not

be a particularly close correspondence between the

values for binding capacity and affinity constant cal-

culated following our experiments and the real

ones. Some hypotheses have been put forward

concerning the biochemical nature of these sites.

By top-down elasticity analysis, we showed that 3,5-

T₂affects the overall kinetics of the reactions in-

volved in the oxidation of substrates by acting on

two different sites in the respiratory chain: namely,

complex IV and the block of reactions involved in

the oxidation of cytochrome c (119). Goglia et al.

(120) found that, in vitro, 3,5-T₂stimulated the ac-

tivity of the COX complex isolated from bovine

Diiodothyronines and mitochondria

Studies concerning the effects of iodothyronines at

the cellular level have been mostly focused on T₃

but, in the last decade, a growing number of resear-

chers have become excited by the possibility that

iodothyronines other than T₃and T₄may be active

in the regulation of energy metabolism. Studies

from several laboratories have suggested that

among these other iodothyronines, 3,5-T₂, a puta-

tive product of the deiodination pathway involved

in T₃metabolism, could be of biological relevance.

905

Iodothyronines and energy metabolism

heart. Later, Arnold et al. (121) used photoaffinity la-

belling to identify subunit Va of the COX complex

as the binding site for 3,5-T₂. Specific binding of

the hormone to subunit Va was then confirmed by

the finding that a monoclonal antibody against sub-

unit Va had an action that prevented the effect of

3,5-T₂. More recently, Kadenbach et al., adding 3,5-

T₂to a reconstituted COX complex, showed a de-

crease in the respiratory control ratio of the com-

plex (measured as the ratio of respiration in the

presence of uncouplers over that in their absence).

This in vitro effect was seen in the presence of in-

traliposomal ATP but not in the presence of intrali-

posomal ADP. On the basis of their data, the au-

thors suggested that either under conditions of low

energy-utilization (high ATP/ADP ratio) as well as

at rest, 3,5-T₂induces a redox-slip in cytochrome

oxidase (122).

ic state of the animal. However, injection of 3,5-T₂

into euthyroid animals results in a slight or non-ex-

istent change in RMR. This could mean that in eu-

thyroid animals 3,5-T₂needs to be formed from a

precursor to be effective in enhancing RMR.

Indeed, very recently we have shown that T₃ad-

ministration to euthyroid rats induces an early ef-

fect on RMR that is independent of actinomycin D

and attributable to the in vivo formation of 3,5-T₂

from T₃(125). We believe that results obtained in

vivo showing 3,5-T₂enhancing the resting me-

tabolic rate of hypothyroid rats via a nuclear-inde-

pendent pathway may be indicative of a physio-

logical role for this iodothyronine in the regulation

of energy metabolism. Interestingly, some recent

studies have shown that 3,5-T₂may have signifi-

cant effects in other species and on other bio-

chemical and physiological parameters. They lead

further support to the notion of a physiological role

There are other mechanisms by which 3,5-T₂might

affect mitochondrial metabolism. Evidence from

Hummerich et al. (100) suggested an influence of

3,5-T₂over mitochondrial metabolism mediated

by an increase in mitochondrial Ca²⁺uptake, which

is known to increase mitochondrial metabolism. In

actual fact, what they showed was that perfusion

of the euthyroid rat liver with T₃or 3,5-T₂led to an

increase in Ca²⁺uptake by the mitochondria. The

effect of T₃, however, disappeared when the per-

fusion was performed in the presence of propy-

lthio uracil (PTU), suggesting that the uptake was

due to 3,5-T₂, not to T₃. The resulting increase in

mitochondrial metabolism seems likely to be due

to an increase in the activity of the mitochondrial

dehydrogenases (41), which would lead to an in-

crease in the amount of reduced substrate avail-

able for the respiratory chain. The above-men-

tioned effects of 3,5-T₂on mitochondria led us to

consider this diiodothyronine as a possible pe-

ripheral mediator of the effect of TH on the ener-

gy metabolism of the whole animal. In our labora-

tory, we have demonstrated that 3,5-T₂, as well as

T₃, is able to enhance the resting metabolic rate

(RMR) of hypothyroid rats, although their effects

differ in terms of both time course and dependen-

cy on protein synthesis (123, 124). Thus, injection

of T₃enhances RMR via a nuclear-mediated path-

way, so its effect takes some days to start and

some days to stop and is blocked by the simulta-

neous injection of actinomycin D (124). 3,5-T₂af-

fects RMR more rapidly, its effect being already ev-

ident 6-16 h after a single injection, and in a man-

ner that is independent of protein synthesis. In

practice, the actions of 3,5-T₂and T₃probably do

not occur independently of each other, they may

rather cooperate in determining the final metabol-

Table 1 - Summary of 3,5-T₂effects both on mitochondrial and

non-mitochondrial parameters.

Effects on mitochondrial parameters

References

99

Increase in oxygen consumption of

perfused rat liver

Increase in oxygen consumption of

mononuclear blood cells

115

Increase in liver mitochondrial respiration

Increase in mitochondrial Ca⁺⁺uptake

112-114

100

Increase in α-glycerophosphate

dehydrogenase activity

125

Increase in respiratory chain activity

Increase in cytochrome oxidase activity

Increase in β-oxidation

118

112,119,120

126

Effects on non-mitochondrial parameters

Increase in malic enzyme activity

125, 127

125

Increase in glucose

6-phosphate-dehydrogenase activity

Inhibition of TSH secretion

128-130

125, 130

131

Stimulation of GH secretion

Increase in deiodinase activity

Increase in leucine metabolism

Increase in cold tolerance of hypothyroid rats

Increase in resting metabolic rate

Influence on lipid peroxidation

126

132

122-124,126

133

Increase in follicle cell volume in

locusta migratoria

134

Inhibition of cancer cell proliferation

135

906

A. Lanni, M. Moreno, A. Lombardi, et al.

for 3,5-T₂. The effects so far attributed to 3,5-T₂

are summarised in Table 1 with the relative refer-

ences.

ner with the T₃nuclear pathway to regulate mitochon-

drial biogenesis and turnover. 3,5-T₂, on the other

hand, seems likely to act directly on the energy-trans-

duction apparatus by binding with some components

of the respiratory chain, thus regulating mitochondrial

respiration (Fig. 2).

CONCLUSIONS

Iodothyronines may influence energy metabolism,

principally by affecting the mitochondrial energy-

transduction apparatus. Both nuclear-mediated and

mitochondrial-mediated pathways are involved in

this effect. Some conflicting results may be found in

the literature and different ideas are supported by

different authors. This may be due to several fac-

tors, of which the wide variety of experimental

methods and conditions used in the various inves-

tigations may be of some importance. Indeed, the

most important of all, in our opinion, are: 1) the

wide range of doses used both in in vivo and in vit-

ro studies; 2) the different animal models used in

studies on hypothyroid conditions (chemical or sur-

gical thyroidectomy) and 3) the fact that most stud-

ies have been performed on liver cells (whose spe-

cial tasks are in intermediary metabolism rather than

in energy expenditure).

Recent reports, however, have advanced our under-

standing of the molecular processes that may be invol-

ved in the action of iodothyronines on the mitochon-

drial apparatus. In particular, it appears that by a nu-

clear-independent pathway, T₃and 3,5-T₂could help

to adapt mitochondrial activity to different physio-

logical conditions. In this pathway, T₃- by binding to

a specific mitochondrial receptor and affecting the

transcription apparatus- may act in a coordinated man-

The nuclear-mediated molecular mechanisms through

which T₃, by regulating the transcription of specific

genes, may influence energy metabolism have consi-

derable impetus received from the discovery that it

may regulate the expression of UCP2 and UCP3. In

particular, the regulation of UCP3 expression in skele-

tal muscle seems to be very promising as a putative

molecular mechanism underlying the regulation of

metabolic rate by T₃. Taken together, these results di-

rect our attention to other questions related to the re-

gulation of energy metabolism. In particular, we need

to know whether the iodothyronines change the me-

tabolic rate in a quantitative (increase in the concen-

trations of enzymes or of components of the respi-

ratory chain, etc.) or in a qualitative manner, or indeed

both. Further, we should now realize that results ob-

tained in vitro in isolated mitochondria or in isolated

enzyme complexes must always be interpreted with

caution. The low degree of reproducibility shown by

the results so far obtained in vitro could be due, at

least in part, to an alteration from the in vivo situation

that could be due to a loss of essential metabolites or

cofactors as well as to the absence of the features of

the physiological environment (such as lipids in the

membrane).

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DOI: 10.1007/BF03343949

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