1) The document discusses mitochondrial DNA (mtDNA) and its role in white adipose tissue. mtDNA encodes components of the mitochondrial respiratory chain and is important for mitochondrial function.
2) Alterations in mtDNA levels or mutations have been linked to obesity and other metabolic disorders. Studies show that mtDNA levels are reduced in obesity but may be more closely associated with diabetes.
3) Drugs that treat diabetes, like pioglitazone, have been found to increase mtDNA levels in white adipose tissue. Further research is needed to fully understand how mtDNA impacts white adipose tissue and metabolism.
Mitochondrial DNA May Play Key Role in White Fat Cell Function and Metabolism
1. reviews nature publishing group
Adipocyte Biology
Mitochondrial DNA: An Up-and-coming Actor
in White Adipose tissue Pathophysiology
Joan Villarroya1,2, Marta Giralt1,2 and Francesc Villarroya1,2
Obesity (2009) 17, 1814–1820. doi:10.1038/oby.2009.152
IntroductIon: MItochondrIal for white adipose tissue biology and the mtDNA gene expression machinery
dna and adIpose cells, systemic metabolic regulation. is distinct from that which deter-
What’s up? Mitochondria in mammalian cells, mines expression from nuclear genes.
The role of mitochondria in white adi- including adipocytes, have a unique Pathogenic processes may alter compo-
pose tissue has traditionally received feature—the mitochondrial genome— nents of the mtDNA-specific expression
little attention. This historic neglect that distinguishes them from other machinery, which is comprised mainly
is based on the assumption that the cellular organelles. This distinct 16-kb of nuclear-encoded proteins that are
white adipocyte’s poor mitochondrial circular DNA-based genetic system transported to the mitochondria after
equipment, being confined to the small encodes mitochondrial components cytosolic synthesis (7). These patho-
cellular space adjacent to the fat drop- that are important for mitochondrial logies may lead to alterations in overall
let, could have little relevance to white function. In mammals, mitochondrial mitochondrial function, altering energy
adipose cell function. In contrast, the DNA (mtDNA) encodes proteins of the balance and disturbing the respiratory
brown adipocyte, which specializes in respiratory chain/oxidative phospho- chain, and leading to enhanced oxygen
thermogenesis, has a robust content of rylation system (OXPHOS) as well as superoxide production or promotion of
mitochondria; thus the role of mitochon- other components of the mitochondrial mitochondrially driven apoptosis—even
drial function in brown adipose cells has translation system (i.e., mitochondrial in the absence of mtDNA mutations.
been recognized as a worthwhile topic transfer RNAs and ribosomal RNAs) Current research coming from the
of study. Brown fat has been tradition- (3). Coordinate regulation of mtDNA- fields of genetics, endocrinology, and
ally considered to play only a minor and nuclear genome–mediated gene pharmacology indicate that mtDNA
role in adult humans, but recent data expression is required for the correct biology may be relevant to white adipose
from positron emission tomography synthesis of a functional mitochondrial tissue function, and suggest that altered
and other tools of nuclear medicine have OXPHOS (4). In addition to its genetic mtDNA in white fat may have local
evidenced the presence of substantial variability in humans, mtDNA is partic- and systemic consequences. However,
amounts of brown adipose tissue in adult ularly susceptible to somatic mutations we are far from having developed a
humans (1,2). Hence, the role of brown that can affect mtDNA-dependent gene full mechanistic understanding of how
adipose tissue in adult human metabolic expression and mitochondrial function. mtDNA alterations cause these effects.
pathologies, such as obesity, has not This is likely due to the direct exposure The present review is intended to pro-
been elucidated but the discovery of pre- of mtDNA to locally produced oxygen vide the first summary of our current
viously uncovered brown adipose tissue superoxides arising from the respiratory knowledge of mtDNA biology in white
in adult humans is expected to stimulate chain as well as to poor performance adipose tissue and how it might be rel-
further research on the role of brown fat of repair systems in mtDNA replica- evant to human pathologies, from obes-
in adult human energy balance. On the tion (5). Tissues from patients bearing ity to lipodystrophy, that are related to
other hand, in recent years, accumulat- mtDNA mutations show a mixture of energy balance.
ing evidence from a number of research mutated and wild-type forms of mtDNA
areas, including studies on obesity, type at a given proportion (heteroplasmy) MItochondrIal dna In
2 diabetes and the lipodystrophies, has and the percentage of mutated mtDNA MaMMalIan cell physIology
highlighted the previously unrecognized is usually associated with the severity of Human mtDNA was first sequenced
relevance of mitochondrial function the pathology symptoms (6). Moreover, in 1981. Since that time, extensive
1
Departament de Bioquimica i Biologia Molecular, i Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; 2CIBER Fisiopatología de la
Obesidad y Nutrición, Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Barcelona, Spain. Correspondence: Francesc Villarroya (fvillarroya@ub.edu)
Received 8 January 2009; accepted 15 April 2009; published online 21 May 2009. doi:10.1038/oby.2009.152
1814 VOLUME 17 NUMBER 10 | OctOBER 2009 | www.obesityjournal.org
2. reviews
Adipocyte Biology
knowledge of the genetics and physi- involved in the control of these processes gene expression, with consequences for
ological processes that rely on mtDNA through interaction with the regulatory mitochondrial function. Several physi-
gene expression in human cells has D-loop region of mtDNA. As shown in ological adaptive processes, such as
become available (3,4). Mitochondrial Figure 1, the control of mtDNA expres- chronic exercise training effects on mus-
DNA in humans encodes two ribosomal sion appears to be directed by nuclear cle, mediate enhanced mtDNA expres-
RNAs, components of mitochondrial gene–encoded transcription factors sion by increasing mtDNA replication
ribosomes; the 22 mitochondrial trans- (e.g., nuclear respiratory factors-1 and and thereby increasing mtDNA gene
fer RNAs; and 13 messenger RNAs that -2), nuclear hormone receptors (e.g., dosage (9). It is not known whether this
are translated into protein components thyroid hormone receptor, estrogen- mechanism of regulation of mtDNA
of distinct complexes of the mitochon- related receptor-α), transcriptional coac- expression through changes in mtDNA
drial respiratory chain and OXPHOS. tivators (e.g., PGC-1s), and corepressors levels occurs in adipose tissue in response
Thus, the energy-producing machinery (e.g., RIP140). These factors control the to physiological adaptations, although it
in mammalian mitochondria relies on expression of nuclear genes that encode takes place in association with brown
respiratory complexes built from nuclear structural components of the OXPHOS and white adipocyte differentiation
and mtDNA-encoded polypeptides, and system and of the nuclear-encoded processes in vitro (10,11), in pathologi-
thus constitutes a unique cellular sys- components of mtDNA replication and cal conditions, and under several phar-
tem that results from the coordinate transcription (TFAM, TFB1M, and macological treatments (see below).
expression of two distinct genomes. TFB2M) (8). The amounts of mtDNA in
However, despite the fact that mtDNA the mitochondria and in the whole cell, MItochondrIal dna In
encodes structural components of the and the extent of mtDNA-dependent adIpocyte developMent and
OXPHOS system, most of the protein protein expression are therefore under dIfferentIatIon
components of the mtDNA replication complex control of nuclear-encoded Until recently, studies on mtDNA biol-
and expression machinery are encoded components of the machinery. In con- ogy in adipose tissue have been limited to
by the nuclear genome. The replication trast with nuclear gene expression, the the analysis of mitochondrial biogenesis
of mtDNA depends on mitochondrial expression of mtDNA genes can not only in brown adipose tissue—the adipose
DNA polymerase-γ, whereas mitochon- be controlled at the level of transcription tissue that specializes in thermogenesis.
drial RNA polymerase is responsible for but also at the level of mtDNA replica- In contrast to white adipocytes, brown
mtDNA-driven transcription. Proteins, tion. Thus, mtDNA gene dosage may adipocytes possess large amounts of
such as TFAM, TFB1M, and TFB2M, are affect the extent of mtDNA-encoded oxidative active mitochondria. During
PGC-1
RIP-140
+ + NRF-2
− +
β
Mitochondria NRF-1
α
mtDNA-encoded Nuclear hormone
OXPHOS proteins receptors (ERRα,...) Nuclear genes
Nucleus
mtDNA replication
Nuclear-encoded
mtDNA-encoded OXPHOS proteins
DNA-Polγ rRNAs/tRNAs mtDNA-encoded
mRNAs
mtDNA mtDNA transcription
TFB1M
mtRPOL
DNA-Polγ TFB2M
mtRPOL
TFAM
figure 1 Schematic representation of the factors involved in the control of mitochondrial DNA (mtDNA) expression. DNA-Polγ, DNA polymerase γ;
ERRα, estrogen-related receptor-α; mtRPOL, mitochondrial RNA polymerase; TFAM, mitochondrial transcription factor A; TFB1M and TFB2M,
mitochondrial transcription factors B1 and B2; NRF-1 and NRF-2, nuclear respiratory factors-1 and -2; OXPHOS, respiratory chain/oxidative
phosphorylation system; PGC-1; peroxisome proliferator–related receptors coactivators; RIP140, receptor interacting protein-140.
obesity | VOLUME 17 NUMBER 10 | OctOBER 2009 1815
3. reviews
Adipocyte Biology
brown adipose tissue development and glitazones increases mtDNA levels in Another important line of research
differentiation, mitochondrial biogen- white fat (18). A study in which mice were is the analysis of mtDNA mutations
esis is enhanced and is accompanied by treated with a diet enriched in polyun- for which there is no direct evidence
increased levels of mtDNA and expres- saturated fatty acids identified mtDNA- for pathogenic consequences, but may
sion of the mtDNA-encoded compo- encoded transcripts and proteins among constitute mtDNA polymorphic forms
nents of the OXPHOS system (10). The the most upregulated genes in white adi- related to obesity. Several reports indi-
transcriptional activators, PGC-1α and pose tissue; this upregulation was associ- cate such association, but no clear-cut
PGC-1β, play an important role in this ated with an enhancement of fatty acid conclusions have been reached to date.
process by coordinately enhancing the oxidation in white adipose tissue (19). The single-nucleotide polymorphism,
expression of nuclear factors that stimu- In humans, the scenario appears to be 15497 G/A, which leads to a glycine-to-
late mtDNA replication and transcrip- more complex. It has been reported that serine amino acid replacement at residue
tion, and regulating the expression of mtDNA levels in adipose tissue are low- 251 (Gly251Ser) in the mtDNA-encoded
specific thermogenic genes (12). ered in type 2 diabetic patients (20), and cytochrome b, has been associated with
Recent studies have highlighted the studies by Arner and collaborators have obesity in a Japanese population (26).
importance of mitochondrial biogenesis confirmed that mtDNA levels are not In fact, individuals bearing the A allele
in white adipose tissue and the potential associated with obesity per se, but rather presented an increased waist-to-hip
for mitochondrial alterations to disturb with type 2 diabetes phenotypes (21). ratio and other obesity-related variables
white adipocyte development and func- Moreover, mtDNA levels were found to including elevated triglyceride levels rel-
tion. Studies by Corvera and collabora- be strongly related to lipogenesis in white ative to individuals bearing the G allele.
tors have shown that (i) mitochondrial adipose tissue (22), rather than to BMI. However, the functional consequences
biogenesis is directly associated with The mechanism by which mtDNA copy of this polymorphism for adipose tis-
white adipocyte differentiation; (ii) obese number in white adipose tissue could sue biology, and whether they affect pri-
ob/ob mice displayed impaired mito- affect lipogenesis rate remains to be marily white adipose tissue function or
chondrial mass and function in white fat; established, but it stands in contrast to the overall energy balance, and thus adipose
and (iii) thiazolidinediones, peroxisome expected relationship between mtDNA tissue expansion, are unknown. Studies
proliferator–activated receptor-γ activa- level variations and energy expenditure of white populations found that this
tors that favor adipocyte differentiation, and fat oxidation. Moreover, in humans, mutation contributes to severe obesity
ameliorated these alterations (13,14). as in rodents, pioglitazone treatment only in rare instances (27), and similarly,
It has been also shown that white adi- causes an increase in mtDNA levels in a polymorphism in the mtDNA D-loop
pocyte differentiation is associated with white adipose tissue of type 2 diabe- noncoding region was not found to be
increases in the relative abundance of tes patients (20) but not in nondiabetic associated with obesity (28). Recently,
mtDNA, and upregulation of compo- obese individuals (23). Probably, one of single-nucleotide polymorphisms in the
nents of the mtDNA replication and the more outstanding pieces of evidence mtDNA-encoded reduced nicotinamide
transcription machinery, such as TFAM in support of the potential relationship adenine dinucleotide dehydrogenase
(11), and components of deoxynucle- between mtDNA levels in white adipose subunit I gene and in the 12S ribosomal
otide metabolism required for mtDNA tissue and human obesity comes from a RNA gene in mtDNA have also been
replication (15). Agents that promote recent study of a series of rare monozy- associated with obesity in a Japanese
white adipocytes differentiation in vitro, gotic twins discordant for obesity (24). population (29) whereas a common
such as glitazones, also increase mtDNA Sequence analyses of mtDNA in subcu- mtDNA variant has been associated with
levels in human adipocytes in vitro (16). taneous adipose tissue revealed no aber- low BMI in white women (30).
rant heteroplasmy between the co-twins.
MItochondrIal dna alteratIons However, mtDNA copy number was MItochondrIal dna pathogenIc
In obesIty reduced by 47% in the obese co-twin’s MutatIons and WhIte adIpose
Studies of potential alterations in white fat. These findings highlight the potential tIssue dIsturbances
adipose tissue mtDNA as they relate role of mtDNA levels in white adipose Since the 1980s, deletions and point
to obesity have focused on two facets: tissue mass. Further research will be mutations in mtDNA have been known
changes in mtDNA levels that underlie needed to clarify the role of mtDNA lev- to cause human diseases. The common
obese phenotypes; and the occurrence els in influencing biological processes in pathogenic features of diseases attributed
of mutated, polymorphic, forms of white adipose tissue beyond the expected to genetic mtDNA alterations involve
mtDNA that are specifically associated consequences on the extent of metabolic defects in neural and muscular tissues,
with obesity. energy consumption through oxidative but not adipose tissues. Nevertheless,
In experimental models of obesity, pathways. However, recent data indicate there is a remarkable exception: muta-
such as ob/ob or db/db mice, abnormally that mitochondrial oxidative capacity tions in the mtDNA-encoded tRNA-Lys
low levels of mtDNA have been reported may not be a major factor determining cause lipomatosis. Most patients bearing
(17,18). As noted above for in vitro events such the extent of free fatty acid pathogenic mutations in the mtDNA-
studies, treatment of obese mice with release by white adipose cells (25). encoded tRNA-Lys (A8344G, T8356C,
1816 VOLUME 17 NUMBER 10 | OctOBER 2009 | www.obesityjournal.org
4. reviews
Adipocyte Biology
G8361A, G8363A) show the myoclonic adipose tissue in association with the body weight through the upregulation of
epilepsy associated with ragged-red fibers accumulation of somatic mtDNA muta- genes facilitating adipocyte lipid storage
syndrome, characterized by neuropathy tions during ageing (42). (49) and, therefore, the impaired peroxi-
and myopathy symptoms. However, some proliferator–activated receptor-γ
other patients show an abnormal enlarge- MItochondrIal dna In expression in adipose tissue from
ment of adipose tissue in the dorsal lIpodystrophIes patients may contribute to lipoatrophy.
area, similar to the Madelung syndrome Research interest in the role of mtDNA However, studies in which antiretro-
(31–34). The lipomatous tissues in the in adipose tissue biology has received a viral treatment of HIV-1 patients with
dorso-cervical area of these patients do dramatic boost in the last few years from lipoatrophy has been interrupted (50)
not show changes in mtDNA levels or in studies of human immunodeficiency or shifted to drugs with a lesser effect
the expression of mtDNA genes. Nuclear virus (HIV) lipodystrophy. This pathol- on DNA polymerase-γ have indicated a
DNA–encoded components of the ogy occurs in a substantial subset of substantial reversion of mtDNA deple-
mitochondria are similarly unchanged, HIV-infected patients under antiretrovi- tion in white adipose tissue but a milder
despite altered expression of master reg- ral treatment; its main features include amelioration of lipoatrophy (51–54).
ulators of adipogenesis. A distorted pat- lipoatrophy of subcutaneous fat, visceral Thus, cause-and-effect relationships
tern of brown vs. white adipocyte gene obesity and, occasionally, lipomatosis. remain unclear. Exposure of brown or
expression, characterized by the expres- A major hypothesis proposed to white adipocytes in culture to nucleo-
sion of the brown adipose tissue–specific account for the etiopathogenesis of this side-analog reverse transcriptase inhibi-
uncoupling protein-1 gene but without lipodystrophy is based on the action tors leads to a reduction in mtDNA as
the acquisition of a complete brown fat of the nucleoside-analog inhibitors of well as to an impairment in adipocyte
phenotype, occurs in the lipomatous tis- the viral reverse transcriptase, a class differentiation (55–57). However, other
sue (35,36). How such a specific muta- of antiretroviral drugs used in HIV-1 antiretroviral drugs that do not inhibit
tion in an mtDNA gene causes adipose infected patients. A side effect of these DNA polymerase-γ nor cause changes
tissue hypertrophy remains a mystery. drugs is inhibition of DNA polymerase-γ, in mtDNA levels, such as protease inhib-
However, it highlights the importance of the enzyme responsible for mtDNA itors, are also powerful blockers of white
mtDNA for the normal development of replication. Accordingly, antiretroviral- adipocyte differentiation in vitro (58).
adipose tissue. treated patients show abnormal reduc- Ultimately, the potential impact of
Certain pathogenic mutations in tions (depletion) in mtDNA abundance mtDNA depletion on cell and tissue
mtDNA are strongly associated with dia- (43). A systematic analysis of published function can be expected to depend
betes caused by progressive insulinope- reports based on cross-sectional studies on the extent to which the depletion
nia, particularly the A3243G mutation indicates that most such studies consist- reduces the levels of mtDNA-encoded
in the mtDNA-encoded tRNA-Leu gene. ently identify an association between gene products. Although mtDNA deple-
This mutation has been associated with mtDNA depletion in subcutaneous tion is usually associated with a reduc-
a low BMI (37,38), and lipomatosis has adipose tissue and lipoatrophy (44). tion in mtDNA-encoded transcripts
been reported in some patients, despite However, other tissues besides white (47), mtDNA-encoded protein levels
good glycemic control (39,40). However, adipose tissue also exhibit a reduction may be unaltered (48,59), suggesting
it is not known to what extent the adi- in mtDNA abundance; thus, if mtDNA the action of compensatory mechanisms
pose disturbances are caused by direct depletion is the cause of the syndrome, it that upregulate the synthesis of mtDNA-
alterations of mtDNA function in white remains unknown why it so specifically encoded proteins. It is worth noting
adipose tissue, or are caused indirectly affects adipose tissue. Perhaps the posi- that mitochondrial mass, as measured
by insulinopenia. tive association between mtDNA levels directly through mitochondrial protein
Finally, one additional piece of evi- and lipogenesis reported elsewhere (22) quantification after mitochondria isola-
dence that support the involvement of may underlie the association between tion (45,59) or indirectly by assessment
mtDNA-related pathologies in altering mtDNA depletion in adipose tissue and of citrate synthase activity (48), may
white adipose tissue is provided by mito- lowered fat mass accretion in subcutane- even be increased in white adipose tis-
chondrial diseases caused by mutations ous white adipose tissue from patients. sue from patients with lowered mtDNA
in nuclear genes involved in the mtDNA The reduction in mtDNA levels occurs in levels. This indicates that, at least in
replication/transcription machinery. conjunction with impaired expression of pathogenic conditions, mtDNA levels
Obesity has been reported to be a fea- genes related to adipocyte differentiation may be dissociated from mitochondrial
ture of Finnish patients with ataxia due (i.e., peroxisome proliferator–activated mass in adipose tissue. However, the
to mutations in mitochondrial DNA receptor-γ), lipid accretion (e.g., lipopro- enhancement of mitochondrial biogen-
polymerase-γ (41). In a parallel experi- tein lipase, GLUT4), and adipokines (i.e., esis in mtDNA-depleted adipose tissue
mental model, transgenic mice bear- adiponectin) (45–48). In fact, thiazolid- does not necessarily lead to enhance-
ing a proof-reading-deficient version of inedione treatment–mediated activation ment of mitochondria functional activ-
the mitochondrial DNA polymerase-γ of peroxisome proliferator–activated ity. The scenario may be similar to the
showed reduced subcutaneous white receptor-γ in humans leads to increased proliferation of abnormal mitochondria
obesity | VOLUME 17 NUMBER 10 | OctOBER 2009 1817
5. reviews
Adipocyte Biology
occurring in skeletal muscle from atrophic subcutaneous adipose tissue (J. Villarroya, M. Hirano, unpublished
patients with mtDNA pathogenic muta- for biopsies and subsequent analysis. data). Another recent report describes
tions and leading to the appearance of Other signs of HIV lipodystrophy, such mtDNA depletion in fat in a mouse
the ragged-red structures in muscle fib- as visceral obesity or lipomatosis are model containing a targeted disruption
ers from these patients (60). The con- not associated with any loss of adipose of the nuclear estrogen-related receptor-α
sequences on bioenergetic mitochondrial tissue mass. A study of biopsies from (ERRα). This receptor appears to play a
function of the enhanced mitochondrial “buffalo hump,” an enlargement of the major role in controlling the expression
mass observed in mtDNA-depleted adipose mass in the dorso-cervical area of nuclear genes involved in mitochon-
white adipose tissue from patients with that occurs in some HIV-1 patients with drial biogenesis; included among these
lipodystrophy have not been extensively lipodystrophy, revealed a depletion of are those related to the mtDNA repli-
studied, but a recent report indicates no mtDNA similar to that found in subcu- cation machinery. Mice lacking ERRα
increase in cytochrome c oxidase activ- taneous lipoatrophic adipose tissue (47). show decreased amounts of white adi-
ity in association with the increased Recently, the availability of samples from pose tissue, abnormal accumulation
mitochondrial mass (48). HIV-1 patient visceral adipose tissue, of brown fat, and resistance to high-fat
On the other hand, even if mtDNA a site prone to enlargement in patients induced obesity (67). Although no data
depletion causes some impairment in with HIV lipodystrophy, revealed also a are available for white fat, the brown fat
respiratory chain, it has been proposed similar reduction in mtDNA levels with from these mice also shows a significant
that its consequences may result not respect to subcutaneous white fat (61). reduction of mtDNA levels and of mtD-
only from lowered ATP production but These observations question the pre- NA-encoded transcripts (68).
also from a reduced synthesis of uridine. sumption that abnormally low mtDNA
An active respiratory chain is required levels could influence the outcome— conclusIons and perspectIves
for the function of dihydroorotate dehy- atrophy vs. hypertrophy—for adipose This summary of the available data pro-
drogenase, a key enzyme in the de novo tissue in a simple manner. vides evidence for a significant role for
synthesis of all intracellular pyrimidines. On the other hand, some reports indi- mtDNA in white adipose tissue biology,
Treatment of white adipocytes with cate that the first signs of mtDNA deple- and indicates that changes in mtDNA
uridine ameliorates the disturbances tion in white adipose tissue occur in the levels and expression of mtDNA-
elicited by drugs that cause mtDNA absence of treatment, simply due to HIV encoded genes in white adipose tissue
depletion, thus suggesting that unaltered infection (62) although most reports may have important consequences in
mtDNA levels are required for correct attribute mtDNA depletion exclusively to multiple pathogenic conditions, includ-
rates of uridine synthesis and that urid- antiretroviral treatment (63). In experi- ing obesity. However, we are far from
ine homeostasis is closely related to the mental rodent models in which there is having a full understanding of the mech-
maintenance of white adipocyte differ- no HIV-1 infection, it has been very dif- anistic issues that relate mtDNA biology
entiation and function (56). ficult to induce mtDNA depletion and and white adipose tissue physiopatho-
It is likely that a reduction in the levels lipodystrophy, even using large doses logy. The relationship between mtDNA
of mtDNA to a certain extent is capable of antiretroviral drugs (64), suggesting and adipose tissue mass is not simple,
of maintaining normal function; at less that HIV-1 infection-related events con- and our present knowledge does not
than permissive levels, a threshold is tribute to the full manifestation of the allow a concise mechanistic explanation
crossed below which white adipocyte mtDNA depletion phenomenon. that reconciles our current knowledge
homeostatic mechanisms cannot ensure Recently, two animal models of of the role of mtDNA in cellular bioen-
unaltered levels of mtDNA-encoded depleted mtDNA have been obtained, ergetics with the complexity of white
gene products. Currently, a precise through targeted disruption or knock-in adipose tissue disturbances associated
understanding of these mtDNA expres- of mutant forms of the gene for mito- with mtDNA changes. Studies of genetic
sion regulatory mechanisms, which are chondrial thymidine kinase-2, the mtDNA diseases in several tissues and
likely to involve the mtDNA transcrip- enzyme responsible for providing deox- organs have provided evidence to sup-
tion and translation machinery, is lack- ythymidine for DNA synthesis inside port the relevance of threshold effects
ing. This is a promising area of research the mitochondria (65,66). In both mod- that relate mtDNA altered levels and
for pharmacological or nutritional inter- els, there was a significant depletion of function with cellular disturbances, and
vention designed to enhance the rates of mtDNA levels in white and brown adi- there are multiple indications that such
mtDNA gene expression, and thereby pose tissue. In addition to a neuromus- threshold effects may be tissue-specific.
ameliorate the pathogenic consequences cular pathology phenotype reminiscent We do not know yet what threshold level
of suprathreshold mtDNA depletion in of human disease in patients with thy- of white adipocyte mtDNA is compatible
white adipose tissue. midine kinase-2 mutations, adipose with the preservation of white adipose
Most studies have focused on relating tissues were also strongly affected, and cell functions. However, certain obser-
mtDNA depletion in fat to white adi- mice showed signs of lipodystrophy vations suggest that changes in mtDNA
pose tissue atrophy in HIV-1 patients. including loss of subcutaneous white fat levels are not solely involved in deter-
This reflects the ease of access to the and abnormal brown adipose tissue (66) mining intracellular oxidative capacities
1818 VOLUME 17 NUMBER 10 | OctOBER 2009 | www.obesityjournal.org
7. reviews
Adipocyte Biology
33. DiMauro S. Mitochondrial diseases. Biochim adipose tissue of HIV-positive HAART DNA depletion and respiratory chain activity in
Biophys Acta 2004;1658:80–88. recipients. Antivir Ther (Lond) 2003;8:323–331. preadipocytes treated with nucleoside reverse
34. Pineda M, Solano A, Artuch R et al. Peripheral 46. Giralt M, Domingo P, Guallar JP et al. HIV-1 transcriptase inhibitors. Antivir Ther (Lond)
neuropathy with ataxia in childhood as a result infection alters gene expression in adipose 2007;12:205–216.
of the G8363A mutation in mitochondrial DNA. tissue, which contributes to HIV- 1/HAART- 58. Gougeon ML, Pénicaud L, Fromenty B
Pediatr Res 2004;56:55–59. associated lipodystrophy. Antivir Ther (Lond) et al. Adipocytes targets and actors in the
35. Vila MR, Gamez J, Solano A et al. Uncoupling 2006;11:729–740. pathogenesis of HIV-associated lipodystrophy
protein-1 mRNA expression in lipomas from 47. Guallar JP, Gallego-Escuredo JM, Domingo JC and metabolic alterations. Antivir Ther (Lond)
patients bearing pathogenic mitochondrial DNA et al. Differential gene expression indicates 2004;9:161–177.
mutations. Biochem Biophys Res Commun that ‘buffalo hump’ is a distinct adipose tissue 59. Nolan D, Hammond E, Martin A et al.
2000;278:800–802. disturbance in HIV-1-associated lipodystrophy. Mitochondrial DNA depletion and morphologic
36. Guallar JP, Vilà MR, López-Gallardo E et al. AIDS 2008;22:575–584. changes in adipocytes associated with
Altered expression of master regulatory 48. Kim MJ, Jardel C, Barthélémy C et al. nucleoside reverse transcriptase inhibitor
genes of adipogenesis in lipomas from Mitochondrial DNA content, an inaccurate therapy. AIDS 2003;17:1329–1338.
patients bearing tRNA(Lys) point mutations biomarker of mitochondrial alteration in human 60. Fukuhara N, Tokiguchi S, Shirakawa K,
in mitochondrial DNA. Mol Genet Metab immunodeficiency virus-related lipodystrophy. Tsubaki T. Myoclonus epilepsy associated
2006;89:283–285. Antimicrob Agents Chemother 2008;52: with ragged-red fibres (mitochondrial
37. Guillausseau PJ, Massin P, Dubois-LaForgue 1670–1676. abnormalities): disease entity or a syndrome?
D et al. Maternally inherited diabetes and 49. Bogacka I, Xie H, Bray GA, Smith SR. Light-and electron-microscopic studies of two
deafness: a multicenter study. Ann Intern Med The effect of pioglitazone on peroxisome cases and review of literature. J Neurol Sci
2001;134:721–728. proliferator-activated receptor-γ target genes 1980;47:117–133.
38. Suzuki S, Oka Y, Kadowaki T et al. Clinical related to lipid storage in vivo. Diabetes Care 61. Villarroya J, Gallego-Escuredo JM, Domingo JC
features of diabetes mellitus with the 2004;27:1660–1667. et al. Differential alterations of gene expression
mitochondrial DNA 3243 (A-G) mutation 50. Kim MJ, Leclercq P, Lanoy E et al. A 6-month in visceral versus subcutaneous adipose tissue
in Japanese: maternal inheritance and interruption of antiretroviral therapy improves from HIV-1-infected, HAART-treated patients
mitochondria-related complications. Diabetes adipose tissue function in HIV-infected patients: with lipodystrophy: a pilot study. Antivir Ther
Res Clin Pract 2003;59:207–217. the ANRS EP29 Lipostop Study. Antivir Ther 2008;13:A3.
39. Suzuki Y, Tsukuda K, Taniyama M et al. (Lond) 2007;12:1273–1283. 62. Lopez S, Garrabou G, Martinez E et al.
Lipoma and sensory neuropathy in 51. McComsey GA, Paulsen DM, Lonergan JT et al. Mitochondrial studies in adipose tissue of
mitochondrial diabetes associated with tRNA Improvements in lipoatrophy, mitochondrial HIV-infected patients without fat redistribution.
mutation at position 3271. Diabetes Care DNA levels and fat apoptosis after replacing Antivir Ther 2004;9:L20.
2002;25:407–408. stavudine with abacavir or zidovudine. AIDS 63. McComsey GA, Libutti DE, O’Riordan M et al.
40. Suzuki Y, Nishimaki K, Taniyama M et al. 2005;19:15–23. Mitochondrial RNA and DNA alterations in HIV
Lipoma and opthalmoplegia in mitochondrial 52. Boyd MA, Carr A, Ruxrungtham K et al. lipoatrophy are linked to antiretroviral therapy
diabetes associated with small heteroplasmy Changes in body composition and and not to HIV infection. Antivir Ther (Lond)
level of 3243 tRNA(Leu(UUR)) mutation. mitochondrial nucleic acid content in patients 2008;13:715–722.
Diabetes Res Clin Pract 2004;63:225–229. switched from failed nucleoside analogue 64. Deveaud C, Beauvoit B, Hagry S et al.
41. Hakonen AH, Heiskanen S, Juvonen V et al. therapy to ritonavir-boosted indinavir and Site specific alterations of adipose tissue
Mitochondrial DNA polymerase W748S efavirenz. J Infect Dis 2006;194:642–650. mitochondria in 3′-azido-3′-deoxythymidine
mutation: a common cause of autosomal 53. Hammond E, McKinnon E, Mallal S, Nolan D. (AZT)-treated rats: an early stage in
recessive ataxia with ancient European origin. Pathogenesis of lipoatrophy: analysis of tissue lipodystrophy? Biochem Pharmacol
Am J Hum Genet 2005;77:430–441. and plasma. Antivir Ther 2008;13:A8. 2005;70:90–101.
42. Trifunovic A, Wredenberg A, Falkenberg M et al. 54. McComsey GA, Lo Re V, O’Riordan M et al. 65. Akman HO, Dorado B, López LC et al.
Premature ageing in mice expressing defective Effect of reducing the dose of stavudine on Thymidine kinase 2 (H126N) knockin mice show
mitochondrial DNA polymerase. Nature body composition, bone density, and markers the essential role of balanced deoxynucleotide
2004;429:417–423. of mitochondrial toxicity in HIV-infected pools for mitochondrial DNA maintenance. Hum
43. Villarroya F, Domingo P, Giralt M. subjects: a randomized, controlled study. Mol Genet 2008;17:2433–2440.
Lipodystrophy associated with highly active Clin Infect Dis 2008;46:1290–1296. 66. Zhou X, Solaroli N, Bjerke M et al. Progressive
anti-retroviral therapy for HIV infection: the 55. Rodriguez de la Concepcion ML, Yubero P, loss of mitochondrial DNA in thymidine
adipocyte as a target of anti-retroviral-induced Domingo JC et al. Reverse transcriptase kinase 2-deficient mice. Hum Mol Genet
mitochondrial toxicity. Trends Pharmacol Sci inhibitors alter uncoupling protein-1 and 2008;17:2329–2335.
2005;26:88–93. mitochondrial biogenesis in brown adipocytes. 67. Luo J, Sladek R, Carrier J et al. Reduced fat
44. Cote HC. Possible ways nucleoside analogues Antivir Ther 2005;10:515–526. mass in mice lacking orphan nuclear receptor
can affect mitochondrial DNA content and gene 56. Walker UA, Auclair M, Lebrecht D et al. Uridine estrogen-related receptor α. Mol Cell Biol
expression during HIV therapy. Antivir Ther abrogates the adverse effects of antiretroviral 2003;23:7947–7956.
2005;10 Suppl 2:M3–M11. pyrimidine analogues on adipose cell functions. 68. Villena JA, Hock MB, Chang WY et al. Orphan
45. Pace CS, Martin AM, Hammond EL et al. Antivir Ther (Lond) 2006;11:25–34. nuclear receptor estrogen-related receptor α is
Mitochondrial proliferation, DNA depletion 57. Stankov MV, Lücke T, Das AM, Schmidt RE, essential for adaptive thermogenesis. Proc Natl
and adipocyte differentiation in subcutaneous Behrens GM. Relationship of mitochondrial Acad Sci USA 2007;104:1418–1423.
1820 VOLUME 17 NUMBER 10 | OctOBER 2009 | www.obesityjournal.org