J Mol Med (2010) 88:1003–1010
DOI 10.1007/s00109-010-0670-x
REVIEW
The role of mitochondria in pulmonary vascular remodeling
Peter Dromparis & Gopinath Sutendra &
Evangelos D. Michelakis
Received: 9 July 2010 / Revised: 4 August 2010 / Accepted: 6 August 2010 / Published online: 24 August 2010
# Springer-Verlag 2010
Abstract Pulmonary arterial hypertension (PAH) is charac-
terized by a hyperproliferative and anti-apoptotic diathesis
within the vascular wall of the resistance pulmonary arteries,
leading to vascular lumen occlusion, right ventricular failure,
and death. Most current therapies show poor efficacy due to
emphasis on vasodilation (rather than proliferation/apoptosis)
and a lack of specificity to the pulmonary circulation. The
multiple molecular abnormalities described in PAH are
diverse and seemingly unrelated, calling for therapies that
attack comprehensive, integrative mechanisms. Similar ab-
normalities also occur in cancer where a cancer-specific
metabolic switch toward a non-hypoxic glycolytic phenotype
is thought to be not only a result of several primary molecular
or genetic abnormalities but also underlie many aspects of its
resistance to apoptosis. In this paper, we review the evidence
and propose that a metabolic, mitochondria-based theory can
be applied in PAH. A pulmonary artery smooth muscle cell
mitochondrial remodeling could integrate a number of diverse
molecular abnormalities described in PAH and respond by
orchestrating a switch toward a cancer-like glycolytic pheno-
type that drives resistance to apoptosis; via redox and calcium
signals, this mitochondrial remodeling may also regulate
critical transcription factors like HIF-1 and nuclear factor of
activated T cells that have been described to play an important
role in PAH. Because mitochondria in pulmonary arteries are
quite different from mitochondria in systemic arteries, they
could form the basis of relatively selective PAH therapies.
This metabolic theory of PAH could facilitate the develop-
ment of novel diagnostic and selective therapeutic approaches
in this disease that remains deadly.
P. Dromparis : G. Sutendra : E. D. Michelakis (*)
Pulmonary Hypertension Program, University of Alberta,
Edmonton, Canada T6G2B7
e-mail: em2@ualberta.ca
Keywords Pulmonary arterial hypertension . Cancer .
Metabolism . Mitochondrial remodeling .
Apoptosis resistance
“This world…ever was and is and shall be, ever-living Fire,
regularly being kindled and regularly going out”—Heraclitus:
On Nature, ∼500 BC
Life is fire produced in mitochondria, and its major fuel,
oxygen, is supplied through the lungs. Mitochondria in the
resistance pulmonary artery smooth muscle cells (PASMCs) are
oxygen sensors and, in response to changes in oxygen tension,
produce redox signals that reach the whole cell and coordinate
the response to hypoxia. The resulting hypoxic pulmonary
vasoconstriction (HPV) is a fundamental property of life and
critical for the maintenance of ventilation–perfusion match in
mammals [1]. While mitochondria are now recognized as
critical for the function of the healthy pulmonary circulation,
evidence emerges that they may also play a critical role in the
diseased state, i.e., pulmonary arterial hypertension (PAH).
The mitochondria-based theory of PAH parallels the emer-
gence of the metabolic theory of cancer [2–5] in which
mitochondria are central to the pathogenesis of the disease.
PAH: mysteries and challenges
PAH is characterized by elevated pulmonary vascular
resistance causing right ventricular (RV) failure and
premature death. An initial endothelial dysfunction (i.e.,
imbalance between vasoconstriction and dilation) and
increased endothelial apoptosis is followed by the devel-
opment of a hyperproliferative and apoptosis-resistant
environment throughout the vascular wall, eventually
causing luminal obliteration [6–8]. PAH primarily affects
1004
the small resistance pulmonary arteries, while the systemic
vasculature remains intact. Current PAH therapies (prosta-
cyclin analogues, endothelin receptor inhibitors, phospho-
diesterase type 5 inhibitors) were originally developed as
vasodilators in systemic vascular disease and thus fail to
address PAH-specific mechanisms. Although these thera-
pies appear to somewhat improve the quality of life of PAH
patients, the prognosis remains poor [9]. There are two
major challenges in the treatment of PAH.
First, the pathogenesis of PAH, which has been reviewed
recently [10–12], is multifactorial. Like in cancer, diverse
molecular abnormalities and environmental triggers have
been described. Among others, they include hypoxia,
viruses, signaling abnormalities in tyrosine kinase receptors,
vasoactive intestinal peptide, epidermal growth factor recep-
tors, angiopoietins, serotonin, Notch or activation of tran-
scription factors like nuclear factor of activated T cells
(NFAT), or hypoxia-inducible factor (HIF). These act on a
predisposed genetic environment that includes germline loss-
of-function mutations in the bone morphogenic protein
receptor II [13] or potassium channel polymorphisms, among
others [14]. Although targeting these pathways in rats or
genetically modified mice may have profound effects, it is
unlikely that attacking a single pathway will reverse PAH in
humans. This diversity and mechanistic complexity calls for
therapies that could address comprehensive and integrative
rather than individual signaling abnormalities.
Second, an ideal PAH therapy should not have extrapulmo-
nary vascular effects. For example, a pro-apoptotic therapy
could lead to aneurysms in systemic vessels or a pro-
angiogenic therapy to retinal or cerebral neo-vessels with
catastrophic consequences. Thus, the identification of
pulmonary-specific targets is important but rarely considered.
One must consider the differences between the pulmonary and
systemic circulations. HPV is one such fundamental differ-
ence. While systemic vessels dilate to physiologic hypoxia, the
pulmonary vessels constrict. HPV is intrinsic to the PASMC of
the resistance pulmonary arteries since they dilate to hypoxia
in the absence of endothelium [1]. Critical oxygen sensors in
the PASMC are the mitochondria, which, under hypoxia,
decrease the production of mitochondria-derived reactive
oxygen species (mROS), inhibiting redox-sensitive potassi-
um channels in the plasma membrane, causing depolariza-
tion, opening of voltage-gated Ca2+ channels, influx of Ca2+,
and constriction[1]. PASMC mitochondria differ compared to
systemic arterial SMC mitochondria, explaining, in part, the
restriction of HPV to the pulmonary circulation [15].
Mitochondria appear to be central in the evolving
metabolic theory of cancer [2–5]. Mitochondria can
integrate several diverse molecular changes and respond
by switching cellular metabolism toward glycolysis, even in
the presence of oxygen (i.e., the Warburg effect), a
condition associated with apoptosis resistance [16]. There
J Mol Med (2010) 88:1003–1010
is evidence that this may occur in PAH as discussed below.
Mitochondria-targeting therapies may reverse a cancer-like
metabolic remodeling and apoptosis resistance while
avoiding extrapulmonary vascular effects, perhaps over-
coming both challenges in PAH therapeutics.
PASMC mitochondria in health and disease
Mitochondria are metabolic sensors and, as such, are
integral in both life (ATP production) and death (apoptosis)
processes [17]. If the fuel demand of proliferative cells
exceeds fuel supply (glucose, lipids, oxygen), apoptosis
may be initiated to preserve fuel or perhaps prevent transfer
of damaged DNA from the oxidative stress of a malfunc-
tioning cell to daughter cells. Mitochondria-dependent
apoptosis maintains metabolic fuel efficiency and homeo-
stasis in a multicellular organism, and its suppression may
offer a survival advantage to proliferating cells.
After its uptake into the cell, the glycolytic pathway
converts glucose to pyruvate in the cytoplasm, anaerobically
producing small amounts of ATP. Pyruvate dehydrogenase
(PDH) serves as a gatekeeper enzyme on the mitochondrial
membrane, catalyzing the decarboxylation of pyruvate into
acetyl-CoA, facilitating substrate entry into the Krebs cycle.
Electrons from the NADH and FADH2, produced by the
Krebs cycle, flow down a redox gradient on the electron
transport chain (ETC) before they reduce O2. During this
process, H+ are secreted out of the inner mitochondrial
membrane, creating the mitochondrial membrane potential
(ΔΨm). This stored energy is used by ATP synthase to
produce ATP. Thus, mitochondrial function (i.e., respiration)
is linked to the degree of ΔΨm, suggesting that ΔΨm could
be a surrogate for mitochondrial function. Since mitochon-
dria are the most negatively charged organelles in the cell
(approx. −200 mV), this can easily be exploited with
positively charged fluorescence dyes (like the rhodamine-
based dyes TMRM and mitoSOX) for the detection of
relatively specific mitochondrial signals. ΔΨm is also
important because it influences mitochondrial-dependent
apoptosis. The voltage-sensitive mitochondria transition pore
(MTP) governs the efflux of pro-apoptotic mediators (i.e.,
cytochrome c) from the mitochondria and opens upon ΔΨm
depolarization [18, 19]. Thus, cells with hyperpolarized
mitochondria are more resistant to apoptosis.
In addition to apoptosis, mitochondrial function is also
closely linked to several other critical cellular functions. As
major producers of mROS, mitochondria can regulate the
cellular redox status. Highly reactive superoxide anions
produced by the ETC can be converted by manganese
superoxide dismutase (MnSOD) to H2O2, which has a
greater diffusible radius and can reach “remote” extrami-
tochondrial targets such as redox-sensitive Kv channels in
J Mol Med (2010) 88:1003–1010
the plasma membrane [20]. Because Kv channels regulate
the plasma membrane potential of the PASMC, their
regulation controls the opening of the voltage-gated Ca2+
channels, the major entry points of Ca2+ for the PASMC, as
mentioned above. Ki+ decreases when the Kv channels
open, and since K+ is a suppressor of caspases, this is
another means by which mitochondria promote apoptosis
[21]. Increased Cai2+ contributes to a proliferative diathesis
of PASMC, in addition to contraction [22]. Due to their
negative ΔΨm and close proximity, the mitochondria can
also directly regulate Cai2+ by uptaking Ca2+ released by
the endoplasmic reticulum [23]. Since mitochondria regu-
late redox and Ca2+-dependent signaling pathways, they
influence a myriad of cellular functions including critical
transcription factors. For example, H2O2 can destabilize
and inactivate HIF [24]. In addition, the Krebs cycle-
derived α-ketoglutarate (α-KG) can leak into the cytoplasm
and regulate HIF since it is a required cofactor for the
prolyl-hydroxylases that destabilize HIF [25, 26]. Thus,
primary changes in mitochondrial function that decrease
mROS and α-KG can stabilize and activate HIF, even in the
absence of hypoxia. Another transcription factor regulated
by mitochondrial signals is NFAT, which is activated either
by an increase in Cai2+ or by inhibition of the metabolic
enzyme glycogen synthase kinase 3β (GSK3β) [27].
Interestingly, both HIF and NFAT can sustain their own
activation by repressing mitochondrial function through the
expression of a number of mitochondrial enzymes [4, 28].
For example, HIF suppresses mitochondrial metabolism by
increasing the expression of pyruvate dehydrogenase kinase
(PDK) [29], a tonic inhibitor of PDH, limiting substrate
entry into the mitochondria. Moreover, HIF promotes
glycolysis by upregulating many glycolytic enzymes
(including hexokinase II (HkII)) and glucose transporters
[4]. In addition to being a rate-limiting enzyme in
glycolysis, HkII translocates to the mitochondria, via a
GSK3β-dependent mechanism, and inhibits the voltage-
dependent anion channel (VDAC) [30, 31], sustaining
mitochondrial hyperpolarization (Fig. 1).
PAH PASMCs have hyperpolarized ΔΨm compared to
healthy PASMCs. This appears to be a common feature
regardless of the cause of PAH. For example, mitochondria
from chronic hypoxia (CH)-induced [32], monocrotaline
(MCT)-induced [32], or from the normoxic fawn-hooded
rats (FHR)-PAH [33] have hyperpolarized ΔΨm and
reduced mROS. Human PAH PASMCs also have hyper-
polarized mitochondria and decreased mROS compared to
healthy PASMCs [34]. Moreover, PAH PASMCs from all of
these models share common molecular abnormalities, in-
cluding downregulated Kv channels, increased Cai2+, and
activation of NFAT and HIF. The downregulation of Kv
channels has been shown to be due to the activation of NFAT
and HIF, closing powerful feedback loops [33, 34]. These
1005
diverse and seemingly unrelated abnormalities underline the
anti-apoptotic and proliferative diathesis of PAH-PASMCs,
which could perhaps be explained by the primary suppres-
sion of mitochondrial function. To understand how this
occurs in PAH, important lessons can be learned from the
recently evolving metabolic hypothesis of cancer.
Lessons from cancer
Cancer cells and PAH-PASMCs have many similarities. For
example, both are locked in apoptosis-resistant states and
several cancer markers are expressed in PAH vessels. Some
of these markers have been shown to play a direct role in
PAH pathogenesis. One example is the cancer marker
survivin, a cell cycle-regulating protein that has additional
anti-apoptotic effects and directly regulates mitochondrial
function as well [35, 36].
Cancer mitochondria are hyperpolarized and have
decreased mROS [37, 38]. In cancer, this is associated
with the suppression of mitochondrial activity, including
glucose oxidation [38]. This results in a metabolic switch
toward cytoplasm-based glycolysis, which is upregulated in
an attempt to “catch up” with the energetically more
efficient glucose oxidation. This has implications beyond
metabolism since almost all glycolytic enzymes also have
additional anti-apoptotic functions [16]. The suppression of
glucose oxidation also allows pyruvate, which is now not
decarboxylated to acetyl-CoA, to remain in the cytoplasm
and either become lactic acid via LDH and generate NAD+,
or be used in anaplerotic reactions used in the biosynthesis
of amino acids, which are required in rapidly proliferating
cells [39]. Kv channel downregulation and NFAT and HIF
activation are also all described in several cancer types [29,
37, 38, 40].
While early in carcinogenesis the cancer cells might be in a
relative hypoxic environment that could explain the glycolytic
phenotype, this is not a sustained condition [41]. Recent
evidence suggests that several diverse primary molecular and
genetic abnormalities all converge, inducing a common
metabolic phenotype where the mitochondria-based glucose
oxidation is suppressed and the cytoplasm-based glycolysis
is upregulated despite the lack of hypoxia [2, 3, 42].
For example, the tumor suppressor p53 regulates cell
metabolism, in addition to regulating cell proliferation [43]. A
loss-of-function of p53 (i.e., one of the most common gene
abnormalities in cancer) suppresses the expression of a
critical component of cytochrome c oxidase [44], thus
inhibiting electron transfer through the ETC. At the same
time, lack of p53 also promotes glycolysis by decreasing
TIGAR (TP53 glycolysis and apoptosis regulator), an
inhibitor of glycolysis [43]. Another common loss-of-
function protein in cancer is phosphatase and tensin homolog
1006
Fig. 1 Metabolic hypothesis of PAH. PAH PASMC mitochondria
have decreased pyruvate influx, hyperpolarized ΔΨm, and reduced
Krebs cycle activity and mROS production. Hyperpolarized ΔΨm and
suppressed mROS close the MTP, “trapping” cytochrome c, and
apoptosis-inducing factor (AIF) in the matrix, resulting in resistance to
apoptosis. mROS suppression closes redox-sensitive Kv channels,
resulting in the accumulation of Ki+, contributing to apoptosis
resistance and Cai2+, resulting in proliferation and contraction.
Suppression of mROS and αKG (Krebs’ substrate) and increased
(PTEN). Inhibition of PTEN activates the Akt axis, inducing
a glycolytic phenotype through a number of mechanisms,
including the GSK3β-medited translocation of HkII to
VDAC [30], resulting in mitochondrial hyperpolarization
and suppression of apoptosis. Another common oncogene,
cmyc, also induces a strong glycolytic phenotype by
upregulating virtually all of the glycolytic enzymes [42].
Abnormalities in several mitochondrial enzymes have
now been described in cancer. Mutations in fumarate
hydratase [45] and succinate dehydrogenase [46, 47]
(Krebs cycle enzymes) have been identified in renal cell
carcinomas and paragangliomas. In these very vascular
tumors, the activation of HIF may in part be due to the
suppression of the mitochondrial signals mROS and α-
KG. Recently, mutations in isocitrate dehydrogenase
(another Krebs cycle enzyme) were identified in glioblas-
toma, a highly vascularized and aggressive tumor [26, 40,
48], further supporting mitochondrial dysfunction in
cancer.
J Mol Med (2010) 88:1003–1010
Cai2+ activate transcription factors (HIF and NFAT) that further
suppress apoptosis and sustain mitochondrial/metabolic remodeling
through gene expression. This whole molecular phenotype is reversed
by the inhibition of PDK (thus activation of PDH) by DCA. In
addition, inhibition of fatty acid oxidation (FAO) indirectly activates
PDH (via the Randle cycle), thus mimicking DCA, also reversing
PAH. *Denotes potential additional targets for therapy predicted by
this mitochondria-centric model of PAH pathogenesis
Increased activity of PDK, resulting in the suppression of
PDH activity, is described in many cancer cell types in vitro
and recently in human glioblastoma in vivo [37, 38]. The
most compelling evidence of the critical role of PDK comes
from the fact that a selective PDK inhibitor, the small
molecule dichloroacetate (DCA), appears to decrease ΔΨm,
increase mROS, and induce apoptosis, decreasing tumor
growth in a number of cancer cell lines and xenotransplant
models [38], but most importantly in humans with glioblas-
toma as well [37] (Fig. 2). Oral therapy with DCA leads to
serum levels high enough to inhibit PDK, increasing PDH
activity in glioblastoma tumors. As predicted, orally admin-
istered DCA in patients with glioblastoma induced apoptosis,
decreased proliferation, and decreased HIF activation,
resulting in decreased tumor growth. Preliminary evidence
suggests that DCA may decrease glioblastoma angiogenesis
in vivo as well [37].
Intriguingly, DCA has reversed every available PAH
rodent model in a similar mechanism to cancer. DCA
J Mol Med (2010) 88:1003–1010
Fig. 2 Mitochondrial modulation with DCA reverses cancer and PAH.
Top row Glioblastoma cells (left) and PAH-PASMCs (right) have
hyperpolarized ΔΨm (TMRM) and are depolarized with DCA (obtained
with permission from [32]). Middle row T1 gadolinium-enhanced axial
MRI images of a glioblastoma patient before and after 9 months of
treatment (left) and H&E-stained medium-sized PAs from DCA or
reversed CH [49], MCT [32], FHR-PAH [33], and PAH in
mice overexpressing serotonin [50]. This was associated
with selective induction of apoptosis in the pulmonary but
not systemic vessels, depolarization of ΔΨm, increased
mROS, and inhibition of HIF and NFAT.
Similar to PDK, there is evidence that other pathways
prevalent in cancer drive this metabolic and mitochondrial
remodeling in PAH. For example, the Akt axis is active in
PTEN KO mice that spontaneously develop PAH [51]. By
extrapolation, identification of other mitochondrial enzyme
mutations in a manner similar to cancer is possible in PAH.
Implications of the metabolic theory of PAH: additional
therapeutic targets
The theory that primary mitochondrial abnormalities drive
apoptosis resistance and several downstream molecular
changes in PAH suggests several targets for drug inter-
ventions (Fig. 1). Targeting the fatty acid oxidation (FAO)
1007
vehicle control chronic hypoxic rats. DCA reduces tumor size and PA
remodeling in vivo (obtained with permission from [37, 49]). Bottom
row DCA induces apoptosis (TUNEL, green) in human glioblastoma
tissue (left) and rat remodeled distal PAs (right) in vivo (obtained with
permission from[32, 37])
pathway may also reverse PAH since inhibition of FAO
indirectly promotes glucose oxidation (by activating PDH,
like DCA) via the Randle cycle. Mice deficient in malonyl-
CoA decarboxylase (MCD), an enzyme critical in promot-
ing fatty acid uptake into the mitochondria, have
suppressed FAO and elevated glucose oxidation under
chronic hypoxic conditions. These mice, which have a
normal phenotype at rest, are resistant to CH-induced PAH,
which may be the result of enhanced glucose oxidation
[52]. In vitro, pharmacological inhibition of FAO with
MCD inhibitors or trimetazidine (TMZ), which is currently
used clinically as an anti-anginal drug, depolarizes ΔΨm
and increases mROS in CH-PASMCs, mimicking DCA. In
vivo, TMZ reversed both CH- and MCT-induced PAH in
rodent models without affecting systemic blood pressure,
once again mimicking DCA. These data support the view
that metabolic modulators may be selective for the
pulmonary circulation [52].
In addition to PDH activators like DCA and TMZ, other
mitochondria targeting drugs may achieve similar efficacy
1008
and selectivity. As predicted by Fig. 1, an MnSOD mimetic
may have beneficial effects by increasing H2O2. Indeed,
MnSOD augmentation with the SOD mimetic MnTBAP
reversed PAH, improving exercise capacity and reducing
RV hypertrophy in FHR [53]. The therapeutic effects of
NFAT inhibitors may also be predicted under the model
shown in Fig. 1. Indeed, cyclosporine depolarizes ΔΨm,
increases mROS, induces apoptosis in PAH-PASMCs, and
reverses rat PAH [34].
This theory is also compatible with the emerging view
that there is a generalized resistance to insulin and a
widespread problem with carbohydrate metabolism in PAH.
In a recent study of non-diabetic females, PAH patients
were more likely to have insulin resistance (triglyceride to
high-density lipoprotein ratio) than controls [54]. Moreover,
insulin-resistant PAH patients had poorer outcomes than
insulin-sensitive patients. Peroxisome proliferator-activated
receptor gamma (PPARγ) agonists are currently used in
type II diabetes to promote insulin sensitivity and glucose
metabolism, but there is evidence that these may be
beneficial in PAH as well [55]. Although this offers further
support to the metabolic theory of PAH, the potential direct
effects of these drugs on mitochondria (which remain
incompletely understood) may be difficult to separate from
the anti-inflammatory effects, which may also contribute
significantly to their therapeutic effects in PAH.
Implications of the metabolic theory of PAH:
diagnostics
The metabolic theory of cancer may also be exploited
diagnostically. Since cancer has a glycolytic phenotype and
uptakes glucose more than healthy tissues, 18-fluoro-2-
deoxyglucose positron emission tomography (18FDG-PET)
is used in the detection of most solid tumors. For example,
glioblastoma tissue has greater 18FDG uptake than normal
Fig. 3 Elevated glucose uptake in
cancer, lung parenchyma in vivo.
a 18FDG-PET superimposed on
T1 axial MRI image of a
glioblastoma tumor. Glioblastoma
tissue (arrow) has higher 18FDG
uptake compared to healthy tissue
(obtained with permission from
[37]). b Idiopathic PAH patients
have higher standardized uptake
values (SUV) of 18FDG in the
lung parenchyma compared to
healthy individuals (obtained
with permission from [56]).
18
FDG-PET was conducted under
fasted conditions in both studies
J Mol Med (2010) 88:1003–1010
brain tissue (Fig. 3). Interestingly, Xu et al. [56] also report
elevated 18FDG uptake in the lungs of PAH patients
compared to healthy individuals, further supporting a
metabolic remodeling in the lung parenchyma (Fig. 3).
While this resemblance of PET imaging in cancer and PAH
is intriguing, potential differences in the clinical protocols
for brain versus lung imaging need to be addressed before
firm conclusions can be reached. Whether 18FDG-PET may
be a reliable diagnostic indicator of PAH requires additional
studies.
Future areas of research
More work is needed with the FAO inhibitors since these
drugs are already clinically available and rapid translation to
PAH clinical trials may be possible. An early-phase clinical
trial with DCA in PAH is in progress (NCT01083524). More
work is also needed to explore metabolism-based imaging as a
diagnostic tool. While the exploration of glucose uptake in the
lungs as a novel biomarker may be limited by the availability
of PET, metabolism can be the target of several imaging
probes that can utilize the widely available SPECT systems for
molecular and metabolic imaging.
While this review largely focuses on the mitochondrial
remodeling in PAH-PASMCs, clonogenic pulmonary artery
endothelial cells (PAECs), which form plexiforme legions,
contribute to the pulmonary vascular remodeling. While
limited studies have investigated mitochondria in these
cells, it is interesting that PAH-PAECs share similar
abnormalities with PAH-PASMCs, including ectopic HIF
activation and increased glycolytic rates [56, 57]. These
findings suggest that similar mitochondrial remodeling may
contribute to the proliferative and apoptosis-resistant nature
of these cells as well and provide the biochemical
explanation for the in vivo PET imaging in patients with
PAH shown in Fig. 3b.
J Mol Med (2010) 88:1003–1010
Although mitochondrial remodeling may be based on
functional changes in specific mitochondrial enzymes such
as PDK or MnSOD, evidence also supports abnormalities
in mitochondrial biogenesis. For example, FHR-PAH
PASMCs have lower mitochondrial density compared to
healthy PASMCs and appear interrupted rather than
filamentous [33]. Lower mitochondrial density was also
reported in PAH-PAECs [56]. In fact, there appears to be a
generalized organelle dysfunction in PAH that includes the
ER and the Golgi [58], perhaps including the mitochondria
as well.
Conclusions
The metabolic remodeling theory offers several new
approaches to PAH. First, it integrates multiple yet
seemingly unrelated pathways involved in the pathogenesis
of PAH since many of these pathways directly or indirectly
involve the mitochondria. Moreover, mitochondrial diver-
sity between the pulmonary and systemic vascular beds
may offer relative selectivity to the pulmonary circulation.
Targeting the metabolic phenotype of PAH may overcome
limitations of current therapies, reversing remodeling
selectively in the pulmonary circulation and also offer
novel imaging and biochemical biomarkers.
Conflict of interest statement The authors declare that they have no
conflict of interests.
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