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Current Medicinal Chemistry, 2019, 26, 3376-3406

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Medicinal
Dietary Polyphenols and Mitochondrial Function: Role in Health and Chemistry

Disease The
International
Journal for
Timely In-depth
Reviews
in Medicinal
Chemistry

BENTHAM
SCIENCE

José Teixeiraa,b, Daniel Chavarriaa, Fernanda Borgesa, Lech Wojtczakc,

Mariusz R. Wieckowskic, Agnieszka Karkucinska-Wieckowskad,* and Paulo J. Oliveirab,*

a
CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto 4169-
007, Portugal; bCNC – Center for Neuroscience and Cell Biology, UC-Biotech, Biocant Park – Cantanhede,
University of Coimbra, Portugal; cNencki Institute of Experimental Biology, Warsaw, Poland; d Department
of Pathology, The Children's Memorial Health Institute, Warsaw, Poland

Abstract: Mitochondria are cytoplasmic double-membraned organelles that are involved in a

myriad of key cellular regulatory processes. The loss of mitochondrial function is related to
 
 

ARTICLE HISTORY
Received: January 04, 2017
Revised: April 23, 2017
Accepted: April 23, 2017
DOI:
10.2174/0929867324666170529101810
the pathogenesis of several human diseases. Over the last decades, an increasing number of
studies have shown that dietary polyphenols can regulate mitochondrial redox status, and in
some cases, prevent or delay disease progression. This paper aims to review the role of four
dietary polyphenols – resveratrol, curcumin, epigallocatechin-3-gallate nd quercetin – in mo-
lecular pathways regulated by mitochondria and their potential impact on human health. Cu-
mulative evidence showed that the aforementioned polyphenols improve mitochondrial func-
tions in different in vitro and in vivo experiments. The mechanisms underlying the polyphe-
nols’ beneficial effects include, among others, the attenuation of oxidative stress, the regula-
tion of mitochondrial metabolism and biogenesis and the modulation of cell-death signaling
cascades, among other mitochondrial-independent effects. The understanding of the chemical-
biological interactions of dietary polyphenols, namely with mitochondria, may have a huge
impact on the treatment of mitochondrial dysfunction-related disorders.

Keywords: Mitochondria, dietary polyphenols, oxidative stress, outer mitochondrial membrane, reactive oxygen
species, electron transport chain.

1. INTRODUCTION by nuclear genes, translated in the cytoplasm and im-

Mitochondria are cytoplasmic organelles found in
the large majority of eukaryotic cells. Mitochondria are
limited by two membranes – the inner (IMM) and the
outer mitochondrial membrane (OMM); each of them
with distinct structure, composition and function [1].
Mitochondria have also their own DNA (mtDNA),
which encodes proteins essential to their activity, even
though many of the mitochondrial proteins are encoded
*Address correspondence to these authors at the CNC – Center for
Neuroscience and Cell Biology, University of Coimbra, UC-
Biotech, Biocant Park 3060-197 Cantanhede, Portugal; Tel:
(+351)231249195; E-mail: pauloliv@cnc.uc.pt and Department of
Pathology, The Children's Memorial Health Institute, Warsaw,
Poland; Tel: (+48)228151964;
E-mail: A.Karkucinska-Wieckowska@IPCZD.pl
*These two authors share senior co-authorship
ported into mitochondria [2]. Mitochondria are classi-
cally viewed as the “powerhouses of the cell” since
they contain the molecular machinery involved in nu-
merous metabolic pathways, such as the Krebs cycle
and the formation of adenosine triphosphate (ATP)
through oxidative phosphorylation (OXPHOS) [3, 4].
Mitochondria are also actively involved in other cell
physiological processes including, but not limited to,
thermogenesis, homeostatic control of cytosolic cal-
cium concentration, apoptosis, innate immune re-
sponses and lipid metabolism [1, 5].
Abnormalities in any of the processes in which mi-
tochondria are involved can be termed as ‘mitochon-
drial dysfunction’ [6]. The loss of mitochondrial func-
tion is implicated in a large number of human diseases.
These include, among others, cardiovascular diseases,

1875-533X/19 $58.00+.00 © 2019 Bentham Science Publishers

Dietary Polyphenols and Mitochondrial Function
cancer, neurodegenerative diseases (e.g. Alzheimer
(AD), Parkinson (PD) or Huntington diseases (HD)),
metabolic (e.g. diabetes, obesity) and autoimmune dis-
eases (e.g. multiple sclerosis, systemic lupus erythema-
tosus) [7, 8]. The mechanisms underlying mitochon-
drial dysfunction in the pathophysiology of the men-
tioned diseases are not completely understood. How-
ever, the development of new therapies aimed to im-
prove mitochondrial function is currently a hot topic
[9]. Over the last decades, attention has been dedicated
to the effects of plant-derived compounds in human
heath, as they are usually consumed in the diet at bio-
logically relevant concentrations [4]. Many of these
compounds can improve mitochondrial capacity and
regulate the apoptotic pathways in health and disease
[10].
Herein, we review the mechanisms of action of
some well-known dietary antioxidants on mitochon-
drial processes as well as their impact on human dis-
eases, including cancer, neurodegenerative, hepatic and
cardiovascular diseases.
2. BIOLOGICAL INTERACTIONS OF DIETARY
POLYPHENOLS
The use of phytochemicals and their benefits in hu-
man health has been known for millennia [11]. Plants
produce a myriad of ubiquitous secondary metabolites,
which bestow metabolic plasticity essential for antici-
pating and responding to biotic and abiotic stress, gen-
erally interpreted as a positive selection of biosynthetic
gene clusters [12]. Among them, polyphenols are con-
sidered to be the most important source of antioxidants
that can be exogenously obtained through human diet
[13]. Polyphenols are characterized by the presence of
at least one phenol function that underlies unique
physical, chemical, and biological properties of particu-
lar class members.
Polyphenols contain a limited number of molecular
scaffolds, but their chemical variability increases with
1) minimal substitutions (e.g. hydroxy and methoxy
moieties); 2) the ability to interact by hydrogen bounds
(among them or with proteins); and 3) the capacity to
polymerise. Together, the different processes originate
more than 4,000 different derivatives [14].
Polyphenols can be classified based on two major
distinguishable subgroups, flavonoids and non-
flavonoids (Fig. 1). Flavonoids include flavonols (e.g.
quercetin), flavones (e.g. luteolin), flavanones (e.g. nar-
ingenin), flavanols (e.g. epigallocatechin-3-gallate
(EGCG)), anthocyanidins (e.g. cyanidin) and isofla-
vones (e.g. genistein) whereas phenolic alcohols (e.g.
Current Medicinal Chemistry, 2019, Vol. 26, No. 19 3377
hydroxytyrosol), phenolic acids (e.g. hydroxybenzoic
and hydroxycinnamic acids), stilbenes (e.g. resvera-
trol), lignans (e.g. pinoresinol), coumarins (e.g. es-
culetin) and chalcones (e.g. butein) belong to the non-
flavonoid subgroup [15].
Fig. (1). Major sub-classes of flavonoid and non-flavonoid
polyphenols.
Dietary polyphenols can contribute to reduce oxida-
tive stress by acting as primary or secondary antioxi-
dants and/or up-regulating endogenous antioxidant de-
fenses (Fig. 2) [16]. In general, polyphenols can act by
controlling reactive oxygen (ROS) or nitrogen (NOS)
species levels, or in other words, by a direct ROS-
scavenging mechanism and/or by a favorable modula-
tion of ROS-removing and redox-regenerating enzyme
activity [17]. Polyphenols can exert a direct radical
scavenging action by reacting with radical species,
such as hydroxyl radical (●OH), superoxide anion radi-
cal (O2●¯), nitric oxide (●NO), alkoxyl radical (RO● )
and peroxyl radical (LO2●), and with non-radical spe-
cies such as peroxynitrite (ONOO-) and hypochloride
acid (HClO). Polyphenols ROS-scavenging activity is
primarily attributed to the presence of phenolic groups
that are capable of donating either one hydrogen atom
or a single electron to ROS and stabilize their level
[18]. Other increasingly recognized mechanism by
which antioxidant polyphenols can operate in vivo is
the ability to upregulate the endogenous antioxidant
defense network, and in particular the ROS-removing
enzymes, in which superoxide dismutases (SODs),
catalase (CAT) and glutathione peroxidase (GPx) en-
zymes are included. Within this process, polyphenols
can also upregulate redox-regenerating enzymes such
as glutathione reductase (GR) and thioredoxin reduc-
tase (Trx) [19]. Polyphenols can also act at the “ROS
formation” level through a direct inhibitory action on
metal-dependent free radical formation, namely on the
3378 Current Medicinal Chemistry, 2019, Vol. 26, No. 19
generation of ● OH and O2●¯, as well as on ROS-
producing enzymes (Fig. 2). A number of polyphenols
are also recognized for their ability to reduce ROS lev-
els by direct inhibition of ROS-producing enzymes,
namely as competitive inhibitors of xanthine oxidase
(XO), an enzyme that is recognized to cause oxidative
injury in post-ischemic reperfusion tissues [17]. Fur-
thermore, some polyphenols can inhibit NADPH oxi-
dase, possibly by interfering with the assembly or the
expression of its various subunits, or inhibit mitochon-
drial-bound monoamine oxidase (MAO) activity [17].
Polyphenols have been proposed to be able to chelate
transition metals such as iron and copper ions inhibit-
ing their role in free radical-generating reactions. The
structure-activity relationship (SAR) studies performed
so far point out a positive correlation between the tran-
sition metal-chelating property and the presence of
catechol and pyrogallol moieties in the polyphenol sys-
tems [20]. The robust polyphenols’ iron-binding prop-
erties are indicative of their effective capacity for
modulating cellular iron homeostasis under physiologi-
cal conditions [16].
Fig. (2). Major known antioxidant-operating mechanisms of
dietary polyphenols. ┬, inhibition; ─●, stimulation.
Increased evidence suggests that polyphenols act in
multiple targets, most of which go beyond a direct an-
tioxidant effect and that still remain to be discovered
[14]. Several reports point out that polyphenols can
modulate pro-inflammatory gene expression, such as
cyclooxygenase, lipoxygenase, nitric oxide synthases,
and several pivotal cytokines regulated by nuclear fac-
tor-kappa B (NF-κΒ) and mitogen-activated protein
kinase (MAPK) signaling [21]. Polyphenols can inter-
act with phospholipid membranes, establishing hydro-
gen bonds and hydrophobic interactions, through their
hydroxyl groups and phenolic rings, and modulate
Teixeira et al.
many by membrane proteins, initiating or regulating
cell signaling processes [22]. Furthermore, polyphenols
can activate AMP-activated protein kinase (AMPK),
which inhibits the mammalian target of rapamycin
(mTOR), a system that is over-activated in ageing and
in chronic diseases. Some plant polyphenols also pre-
sent significant anticancer properties, consistent with
the activation of endoplasmic reticulum (ER) stress and
the unfolded protein response (UPR) signature, sirtuin-
1 (SIRT-1) activation, AMPK upregulation and epithe-
lial-to-mesenchymal (EMT) transition inhibition [14,
23]. Furthermore, the effect of polyphenols on age-
related neurological disorders suggests that polyphe-
nols regulate multiple signaling pathways, including
Pi3K/Akt, Nrf2/HO-1, PPAR, STAT, NF-κΒ, HIF, and
MAPK. Although a wide variety of mechanisms of ac-
tion account for polyphenols effects, most of them are
interconnected due to the pleiotropic character of the
pathways and proteins involved [24].
3. DIETARY POLYPHENOLS AND MITO-
CHONDRIA
3.1. Mitochondrial Generation and Processing of
Reactive Oxygen Species (ROS)
The mitochondrial respiratory chain, the last com-
ponent of which is cytochrome c oxidase, catalyzes a
four-electron reduction process of molecular oxygen
(O2) to form water. However, small quantities of elec-
trons “leak out” at various redox sites of the respiratory
chain resulting in a small, but significant, one-electron
reduction of O2 yielding O2●¯. According to a rough
estimation, about 1% of the total oxygen uptake in
mammalian tissues may end up as free radical. The su-
peroxide anion, or its protonated form HO2●, can dis-
mutate to form hydrogen peroxide (H2 O2). In the pres-
ence of transition metal cations, such as Fe2+ or Cu+,
hydrogen peroxide reacts through the Fenton reaction,
yielding the extremely reactive ● OH. The two free
radicals, O2●¯ and ●OH, along with H2 O2, singlet oxy-
gen 1O2, formed in some photochemical reactions,
ozone (O3), an air pollutant, are species chemically
more reactive than O2. Among ROS, only O2●¯, H2O2
and, under specific conditions, ●OH are physiological
metabolites. It is now generally settled that the main
sites of O2●¯ generation in the mitochondrial electron
transport chain (ETC) are complexes I and III [25, 26].
Apart from that, ROS may be produced within the mi-
tochondrion by 2-oxoglutarate dehydrogenase, sn-
glycerophosphate dehydrogenase, cytochrome b5 re-
ductase and monoamine oxidase. In addition, signifi-
cant amounts of ROS can be produced outside mito-
Dietary Polyphenols and Mitochondrial Function
chondria in neutrophiles, namely in the ER and perox-
isomes, during the oxidation of long-chain fatty acids,
[27] and by NADPH oxidase at the plasma membrane
[28]. Various ROS forms can also be generated within
the cell by the action of ionizing and ultraviolet radia-
tion and xenobiotics, namely pharmaceuticals [29], e.g.
the chemotherapeutic agent doxorubicin, and herbi-
cides, such as paraquat. Also, heavy metal cations such
as Cd2+, Hg2+, Pb2+ and Cu2+ induce ROS production in
affected tissues and organs [30]. Increased ROS gen-
eration can also occur in aging [31, 32] and under
pathological conditions such as inflammation [33], hy-
poxia followed by reperfusion [34] and in neurodegen-
erative diseases, including AD [35] and PD [36], al-
though the mechanisms of these processes are, in gen-
eral, poorly elucidated. Increased ROS production is
also observed after a temporary decrease of oxygen
tension (anoxia or hypoxia) followed by re-
oxygenation, a process that occurs, for instance, during
the reperfusion that follows cardiac ischemia (for more
information see also [37]). Despite their traditional
negative image, ROS are generated as by-products of
normal metabolism and as the second messengers in
various signaling pathways. ROS are heterogeneous in
origin and can exert their beneficial or detrimental ef-
fects depending on the concentration and cellular com-
partment at which they are present or produced [38].
The long-term overproduction of ROS can occur due to
a diversity of endogenous factors such as dysregulated
metabolism, affected antioxidant defense system and
inflammation or exogenous environmental factors such
as chemical exposure, pollution or radiation. Such im-
balance between ROS generation and antioxidant en-
dogenous defense mechanism can result in oxidative
stress, a process that may cause irreversible damage to
DNA, proteins, and lipids. Superoxide anion can react
with lipids, primarily by attacking double bonds of un-
saturated fatty acid, and with proteins and nucleic acids
creating a redox imbalance in mitochondria. A dismu-
tation reaction can convert O2●¯ into H2O2. The damage
caused by H2 O2 to cellular integrity and viability is re-
lated to two properties: first, it readily crosses biologi-
cal membranes, in contrast to the limited permeability
of O2●¯; and, it can generate the highly reactive hy-
droxyl radical, in the presence of transition metal
cations [38].
In the human body, each cell maintains a condition
of homeostasis between oxidant and antioxidant spe-
cies [39]. There are several systems decomposing ROS
and thus protecting the cell against its noxious actions.
The protective mechanisms include a number of low-
molecular weight antioxidants and enzymatic systems.
Current Medicinal Chemistry, 2019, Vol. 26, No. 19 3379
The former category includes nutritional compounds
(vitamins) such as ascorbic acid (vitamin C), α-
tocopherol (vitamin E), and β-carotene (pro-vitamin
A), as well as intrinsic cellular small proteins and co-
factors, namely reduced glutathione (GSH) and re-
duced pyridine nucleotides NADH and NADPH. Anti-
oxidant enzymes, such as SODs, CAT and several per-
oxidases, also belong to the endogenous antioxidant
defense systems, which can catalyze complex cascades
of reactions that convert ROS into more stable and
harmless molecules. The reactions are normally initi-
ated by SODs with detoxification of O2●¯, which dis-
mutates O2●¯ to H2 O2. The mitochondrial isoform of
this enzyme, located in the mitochondrial matrix, con-
tains a manganese atom in its active center (Mn-SOD;
SOD2), whereas the cytosolic enzyme (also present in
the mitochondrial intermembrane compartment), con-
tains zinc and copper atoms (Cu,Zn-SOD; SOD1).
Therefore, the next step is related to the removal of
H2 O2 by CAT, a heme enzyme present in peroxisomes
of various tissues that transforms H2 O2 into H2O and
O2. Hydrogen peroxide can also be decomposed by
peroxidases that transfer the oxygen atom to an organic
acceptor. Glutathione peroxidases present in the mito-
chondrial matrix containing selenocysteine in their ac-
tive centers constitute the key enzymatic network used
to remove H2 O2 from the mitochondrial matrix. The
enzymatic system effectiveness is maintained by high,
millimolar, intramitochondrial concentration of re-
duced glutathione. Under normal conditions, all these
ROS-metabolizing processes can maintain intramito-
chondrial steady state concentrations of O2●¯ and H2O2
at physiological submicromolar levels. Notwithstand-
ing, “classic” oxidative stress may occur when an ex-
cessive production of ROS and/or a deficiency of en-
zymatic and non-enzymatic endogenous antioxidants is
found in biological systems [38].
3.2. Dietary Polyphenols: From Protecting to Dam-
aging Mitochondria
A number of polyphenolic compounds present or
added as appetizers, or spices in small quantities in
food, can act as ROS scavengers. Their effectiveness as
ROS scavengers is documented mostly in tissue and
cell cultures. However, the knowledge of their effec-
tiveness in the whole organism is much less certain and
often controversial. Moreover, their poor absorption
from the intestinal tract results in a low concentration
in body fluids [40, 41]. As dietary polyphenols are a
large group of compounds with a great chemical diver-
sity, the present review focused on four of the most
3380 Current Medicinal Chemistry, 2019, Vol. 26, No. 19
popular dietary polyphenol antioxidants: resveratrol,
curcumin, EGCG and quercetin.
3.2.1. Resveratrol (Fig. 3A)
A polyphenol of natural origin. It is present in the
skin of some fruits such as grapes, blueberries, raspber-
ries and mulberries, and red wine. It is speculated that
resveratrol is, among other factors, responsible for the
beneficial role of the Mediterranean diet on human
health [42, 43]. Nevertheless, according to the prevail-
ing general opinion there is no evidence that consum-
ing resveratrol-rich foods or taking resveratrol as a die-
tary supplement has any health effects on humans [44].
The studies performed so far on the effects of resvera-
trol on mitochondria that are mostly based on studies
on isolated mitochondria and cell cultures (for recent
review see [9]). The results are controversial, not ena-
bling to build a clear picture of the biological effect of
this compound. For example, resveratrol has been
found to inhibit oxygen uptake by isolated mitochon-
dria and to block the electron transport at the level of
complexes I and III of the mitochondrial respiratory
chain [45]. Consequently, an increased “electron leak”
was observed, and in turn an increased ROS production
[46]. On the other hand, other authors (e.g. [47]) re-
ported that the antioxidant effects of resveratrol on iso-
lated mitochondria are related to a direct ROS scaveng-
ing activity. The picture is more complex as resveratrol
A Resveratrol
OH
HO
OH
C Epigallocatechin-3-gallate (EGCG)
OH
OH
HO O
OH
O OH
OH OH
O
OH
OH
Fig. (3). Chemical structure of dietary natural polyphenols. A) Resveratrol; B) Curcumin; C) Epigallocatechin-3-gallate
(EGCG); and D) Quercetin.
Teixeira et al.
can inhibit F1Fo-ATP synthase/ATPase [48], an effect
that may result in either in the increase or decrease of
ROS production, depending on whether the electron
flow is inhibited or accelerated. Resveratrol has been
found to induce apoptosis in several malignant cell
lines [49, 50]. However, controversy exists on whether
this process was mitochondria-dependent, i.e. related to
the release of cytochrome c from mitochondria to the
cytosol and to the activation of caspase 9 [51]. Never-
theless, the effective resveratrol concentration used in
the study was in the micromolar range, a concentration
difficult to be attained in the living organism.
3.2.2. Curcumin (Fig. 3B)
A polyphenol of natural origin, and a component of
the rhizome extract of turmeric Curcuma longa, a
South Asian plant. Curcumin is a component of the
yellow pigment of curry, a common Indian spice that is
also used in the traditional Asian medicine, particularly
for skin diseases, as well as other diseases [52]. How-
ever, because of its poor absorption in the alimentary
tract, the bioavailability when administered orally is
questionable. It can be speculated that some of the ob-
served beneficial effects of curcumin can be ascribed to
its metabolites and degradation products [53]. During
in vitro experiments with cell cultures curcumin has
been recognized as an anti proliferative and antineo-
plastic agent [54-60], able to induce apoptosis in hu-
B Curcumin
OCH3O OCH3
HO OH
O OH
D Quercetin
OH
OH
HO O
OH O
Dietary Polyphenols and Mitochondrial Function
man hepatoblastoma and leukemia cells [61, 62]. How-
ever, curcumin has also been shown to prevent apopto-
sis in different cell types [63] or to induce mitochon-
drial-independent apoptotic pathway [64]. This vari-
ability of data is probably dependent on different
treatment protocols and models used. Due to its par-
ticular chemical structure, curcumin is a scavenger of
ROS. However, curcumin multiple pharmacological
profile, ranging from antineoplastic action [65],
through anti-inflammatory [66] and anti-obesity effects
[67, 68] to anti-aging action in some model animals
[69], is difficult to be explained by a simple mecha-
nism. It has been proposed that some of these processes
are mediated by multiple mechanisms involving inter-
ference in signal transduction [70] and gene expression
[71] pathways.
3.2.3. Epigallocatechin-3-gallate (EGCG) (Fig. 3C)
Chemically a catechin (2R, 3R)-2-(3,4,5-trihydroxy-
phenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-
(3,4,5-trihydroxybenzoate) derivative, EGCG is the
most abundant catechin of green tea (Camellia sinensis
L.). Its concentration was estimated to be between 9 to
13% of the total amount of catechins present in green
tea [72]. EGCG is considered the main component,
more than 50%, of the polyphenolic fraction, of green
tea [73]. Antioxidant properties of EGCG are related to
the presence of the phenolic groups present in the fla-
vonoid moiety as well as the presence of hydroxyl
groups in the exocyclic aromatic ring [74]. Unfortu-
nately, EGCG is not a stable molecule in solution, and
depending on the concentration, pH, temperature, and
other factors, EGCG can undergo auto-oxidation and
epimerization processes. Different O-methylated de-
rivatives of EGCG are present in the green tea leaves,
but their levels and ratio depend on different factors
including the type of green tea, the age of leaves and
season of harvesting and fermentation process. More
information about this issue can be found in the recent
papers of Oliveira et al. and Wong et al. [73, 75]. The
effects of EGCG on isolated mitochondria as well as on
mitochondrial function in vivo were described in detail
by Oliveira et al. [73]. Apart of its multiple beneficial
effects described in the literature, the authors also re-
port that EGCG can also have negative effect on mito-
chondrial function [73].
3.2.4. Quercetin (Fig. 3D)
A polyphenol belonging to the class of flavonols
that is present in edible parts of numerous plants, in-
cluding onion, asparagus, broccoli and peas. Among
fruits, apples contain the highest amounts of quercetin.
Current Medicinal Chemistry, 2019, Vol. 26, No. 19 3381
In plants, quercetin is mostly present as glycosides,
from which it is liberated in form of the free aglycone
in the intestinal tract of humans and other mammals.
After absorption, quercetin undergoes glucuronidation,
methylation or sulphation metabolism in animal and
human tissues. The total concentration of quercetin,
and its derivatives, in human plasma is in the nanomo-
lar range but it can be increased to the low micromolar
range through dietary supplementation [76]. The
bioavailability of quercetin ingested from food is, in
general, low. Due to its particular chemical structure,
quercetin is a potent scavenger of ROS and RNS spe-
cies [77]. However, its role as an effective pharmacol-
ogical antioxidant is questionable because of its low
concentration in the plasma and tissues, much lower
than that of ascorbic acid and reduced glutathione. It is,
therefore, suggested [76] that some of the observed
pharmacological effects are dependent on its capacity
of modulating the cell’s own antioxidant mechanisms.
One of the possible mechanisms is the activation of the
pathway mediated by nuclear factor (erythroid-derived
2)-like 2 (Nrf2) [78] that regulate the expression of an-
tioxidant enzymes. Another mechanism involved is
mitochondrial ROS level regulation via paraoxonase 2
(PON2) pathway [79, 80]. Among other quercetin bio-
logical effects, its neuroprotection properties, which are
mediated for example by the activation of sirtuins and
apoptosis inhibition, have been considered [76, 81].
However, it must be kept in mind that most of these
protective and beneficial effects, if not all, have been
observed in in vitro cell studies. Due to the lack of ro-
bust evidences the European Food Safety Authority
concluded that, although “the protection of DNA, pro-
teins and lipids from oxidative damage may be a bene-
ficial physiological effect”, the claimed effects of quer-
cetin on the cardiovascular system, liver, kidneys and
mental state and performance are general and non-
specific and do not refer to any specific health claim as
required by Regulation (EC) No 1924/2006” [82].
3.3. Dietary Polyphenols-Associated Mitochondrial
Toxicity
Cellular metabolism strongly depends on mitochon-
dria and the proper exchange of metabolites across or-
ganelle membranes. In fact, mitochondria perform the
biosynthesis of amino acids, vitamins, lipids, prosthetic
groups and many other intermediates, which are re-
quired for OXPHOS and cell viability [83]. Although a
wide variety of antioxidant mechanisms has been pro-
posed to polyphenols most of them are interconnected
due to the pleiotropic character of the pathways and
proteins involved [24]. Given the importance of mito-
3382 Current Medicinal Chemistry, 2019, Vol. 26, No. 19 Teixeira et al.

chondria on the regulation of the cellular redox homeo-
stasis, the modulation of mitochondrial processes by
polyphenols has been recently recognized as a hot
topic, in particular their interaction with ETC com-
plexes, complex V and consequent on ATP synthesis
and mitochondrial membrane potential (mΔΨ) (Fig. 4)
[17].
3.3.1. Electron Transport Chain (ETC)
OXPHOS couples the ETC with the ATP synthase
(complex V) activity in a process that involves redox
reactions and transmembrane proton translocation.
Conditions that can lead to a decrease of activity of any
of ETC complexes have been associated with a sub-
stantial increment in O2●¯ production within mitochon-
dria [84, 85]. The potential of dietary polyphenols to
interact with some ETC complexes has been described.
Studies reported that quercetin inhibited complex I ac-
tivity in rat brain mitochondria (RBM) (10-100 μM
range) [86]. Also, resveratrol was shown to inhibit
complex III in isolated RBM (IC50 = 5.49 nM) [45].
3.3.2. ATP Synthesis
Intra mitochondrial ATP synthesis is mainly driven
by complex V. Structurally, complex V resembles a
rotating motor and contains two main parts, an inner
mitochondrial membrane-embedded Fo base and a
globular F1 headpiece, both of which are linked by a
common rotor shaft which couples proton flow to ATP
synthesis. Clockwise rotation of the γ -subunit of F1
allows ATP synthesis, whereas the anti-clockwise rota-
tion allows complex V to work as an ATPase [87].

Fig. (4). Schematic representation of the main mitochondrial actions of polyphenols. Polyphenols such as resveratrol, cur-
cumin, EGCG and quercetin can induce mitochondrial biogenesis, induce or inhibit the triggering of intrinsic apoptosis, modu-
late the opening/or closure of the mPTP, uncouple oxidative phosphorylation (OXPHOS) and inhibit complex V activity. In
addition, some of compounds are also able to inhibit complexes I, II or III of the mitochondrial electron transport chain (ETC).
BAK: Bcl-2 homologous antagonist/killer; BAX: BCl-2-associated protein X; cyt c: cytochrome c; IMS: intermembrane space;
MMP: mitochondrial membrane permeabilization; mPTP: mitochondrial permeability transition pore; PGC-1α: Peroxisome
proliferator-activated receptor gamma coactivator 1-alpha; ROS: reactive oxygen species; SIRT1: Sirtuin 1; TIM: translocase
of the inner membrane; TOM: translocase of the outer membrane
Dietary Polyphenols and Mitochondrial Function
Several polyphenols have been reported to inhibit
complex V activity. The flavonol quercetin was shown
to inhibit ATPase activity of complex V, but not its
ATP synthase activity [48]. Other study has shown that
resveratrol, EGCG and curcumin were all effective in
the inhibition of RBM complex V ATPase activity
[48]. Furthermore, resveratrol was also shown to in-
hibit the ATP synthase activity of complex V. Mecha-
nistically, it was proposed that resveratrol and quer-
cetin can bind, via hydrogen-bonds and hydrophobic
interactions, to a common site in the inside surface of
F1 subunit. Contrarily to quercetin that only inhibits the
anti-clockwise movement of the γ -subunit, resveratrol
can interfere with both directions of the rotation
(clockwise and anti-clockwise) exerting ATP synthase
and ATPase inhibitory activities [88].
3.3.3. Mitochondrial Membrane Potential (mΔΨ)
According to the chemiosmotic theory, the exis-
tence of a proton-impermeable IMM is a required con-
dition for the energy transduction between complexes
of ETC and the H+ driven synthesis of ATP. Addition-
ally, the maintenance of proper IMM and OMM struc-
tures are also vital for cell survival. Despite this, two
important processes exist under physiological condi-
tions that are able to induce alterations of membrane
permeability: 1) transport of protons from the inter-
membrane space (IMS) into the matrix through uncou-
pling proteins, which primarily dissipate the mΔΨ, and
2) membrane permeability transition phenomena in-
duced by the opening of the multiprotein complex mi-
tochondrial permeability transition pore (mPTP), which
involves a major permeabilization of the IMM [89].
Actually, some dietary polyphenols have also been re-
ported to induce mitochondrial uncoupling and/or to
modulate mPTP. For instance, in a study Trumbeckaite
et al. [90] reported that quercetin was effective in
stimulating state 2 respiration in rat heart mitochondria.
Interestingly, the apparent OXPHOS uncoupling effect
of quercetin was observed at a concentration two-to-
three order of magnitude lower than those reported to
be attained in human plasma after the consumption of
quercetin-rich foods [91]. Furthermore, some dietary
polyphenols have also been described to be modulators
of the mPTP opening. For instance, quercetin can act
both as an inhibitor (5 μM) and as an inducer (40 μM)
of mPTP opening depending on the experimental con-
ditions and on the flavonoid concentration [92]. A po-
tential pro-oxidant mechanism, in which quercetin can
undergo an oxidation process with formation of qui-
none-derivatives, is believed to underlie its mPTP-
inducing activity [92, 93].
Current Medicinal Chemistry, 2019, Vol. 26, No. 19 3383
4. DIETARY POLYPHENOLS AND DISEASE: A
ROLE FOR MITOCHONDRIA?
Oxidative stress-related diseases prevalence, mor-
bidity, and mortality represent a significant medical,
social, and financial burden to the society. Conse-
quently, considerable efforts have been put into the
search and/or development of antioxidants, namely
those of natural origin, which can reduce ROS levels
and/or prevent ROS-induced damage. In general, a
regular and well-balanced diet contains all the nutrients
needed for a healthy body. However, under metabolic
and/or mitochondrial disruption processes, dietary sup-
plementation, e.g. with vitamins and dietary polyphe-
nols, can be required. Beneficial effect of this type of
supplements is still controversial and under debate.
Comprehensive information about the effect of dietary
polyphenols on cellular metabolism can be found in the
recent review of Amiot et al. [94]. Overwhelming evi-
dence from epidemiological, meta-analysis and pre-
clinical trial data indicates that a polyphenol-enriched
diet can be associated with a reduced incidence of
chronic diseases [18]. Experimental data have provided
evidence that the intake of dietary polyphenol antioxi-
dants can be beneficial to decrease oxidative stress and
that at least some of them can exert beneficial effects
on mitochondrial disorders, cancer, cardiovascular and
neuronal diseases by activating adaptive stress response
signaling pathways (Fig. 5) [95-97].
Fig. (5). Dietary intake and distribution of natural
polyphenols. Despite their low bioavailability, polyphenols
may pass into the bloodstream after the consumption of
polyphenol-rich foods and beverages and gut absorption. The
compounds that enter in circulation are able to reach several
tissues such as heart, brain and liver, protecting them from
the oxidative damage.
3384 Current Medicinal Chemistry, 2019, Vol. 26, No. 19
4.1. Mitochondrial Respiratory Chain Diseases
Mitochondrial disorders such as Leigh’s and
Leigh’s-like syndromes, Leber’s hereditary optic neu-
ropathy (LHON), neurogenic muscle weakness, ataxia
and retinitis pigmentosa (NARP), mitochondrial en-
cephalomyopathy, lactic acidosis and stroke-like epi-
sodes (MELAS), chronic progressive external oph-
thalmoplegia (CPEO), Kearns-Sayre syndrome (KSS),
myoclonic epilepsy with ragged-red fibers (MERRF) as
well as other diseases including PD, AD and diabetes
are associated with mitochondrial dysfunction and very
often related with oxidative stress. Up to now there are
no therapeutic solutions for mitochondrial disorders
and other mitochondrial dysfunction-associated dis-
eases. However, a diversity of compounds such as co-
enzyme Q10, creatine, methylene blue, idebenone, mi-
toQ, mitoTEMPOL, mitovitE, and curcumin have
shown positive effects when tested for instance in AD
patients categorized with multiple mitochondrial de-
fects [98, 99]. In general, this type of compounds act in
multiple sites and modulate the status of intracellular
oxidative stress. A comprehensive review of their
mechanism of action has been presented by Kumar et
al. [100]. For some mitochondrial disorders, coenzyme
Q10 is used as a supplement, although its efficacy is
still not consensual. Moreover, a more complex picture
is expected as a treatment that has a positive effect in
one particular mitochondrial defect may be completely
ineffective in other. Actually, in some cases, the dietary
supplementation can have a negative effect.
4.1.1. Resveratrol
Based on the observation that resveratrol inhibits
mitochondrial complexes I and III in isolated mito-
chondria [45], it was suggested that in the case of a mi-
tochondrial defect based on a respiratory chain defect,
resveratrol supplementation can be hazardous and may
worsen the bioenergetic deficit. However, Mathieu et
al. [101] has shown that resveratrol can decrease oxida-
tive stress in the case of mitochondrial complex I defi-
ciency and what is more important, resveratrol supple-
mentation can restore oxygen consumption in complex
I-deficient patient cell lines [101, 102] and increase
NADH oxidation [103]. The role of resveratrol on
AMPK, Sirt1 and Sirt3 activation in the metabolic ad-
aptation of human cells harboring mtDNA mutations
was reviewed by Wu et al. [104]. Controversially,
other studies have demonstrated that resveratrol can
inhibit mitochondrial ATP synthase, possibly by de-
creasing ATP production, being a risky approach for
individuals having defects on ATP synthesis [88].
Teixeira et al.
More details about the effect of resveratrol on cellular
metabolism can be found in Bitterman and Chung
[105].
4.1.2. Curcumin
Apart from antioxidant properties, curcumin has
also been shown to have positive effects on OXPHOS
components and may be beneficial for patients harbor-
ing mitochondrial respiratory chain dysfunction. Raza
et al. [106] have shown that curcumin can protect mi-
tochondrial respiratory chain against the pro-oxidative
effect of 4-hydroxynonenal, a byproduct of lipid per-
oxidation [106]. Moreover, curcumin was able to pro-
tect rat cortical neurons treated with tert-butyl hydrop-
eroxide (t-BHP) against cytochrome c release and
caspase-3 activation [107]. Animal studies conducted
by Kumar et al. [108] have shown that curcumin was
able to restore complexes I, II and III activity, which
were inhibited by chronic administration of D-
galactose. Interestingly, curcumin has increased the
expression of mitochondrial ATP synthase, resulting in
augmented ATP level, in brain of diabetic rats [109].
The negative effect of curcumin on mitochondrial res-
piratory chain has not been reported yet. However, cur-
cumin safety is still a controversial subject [110].
4.1.3. EGCG
This polyphenolic system abundant in green tea has
been described as a cytoprotective agent. EGCG effects
were generally mediated by its antioxidant properties
and ability to induce Nrf2-dependent gene expression
[111]. EGCG positive effects on OXPHOS, via in-
duced mitochondrial biogenesis in fibroblasts of
Down's syndrome (DS) individuals with impaired mi-
tochondrial complex I [112] and ATP synthase [113],
have also been documented by Valenti et al. [114]. The
authors found that EGCG restored the activity of com-
plex I and ATP synthase, increasing mitochondrial
ATP production and reducing oxidative stress in DS
patient fibroblasts. Such strong positive effect was not
noticeable when the cell culture growth medium was
supplemented with galactose, instead of glucose, to
drive OXPHOS as the main source of ATP. However,
in these studies EGCG showed a positive effect on the
total cellular ATP content, an effect that was related to
a higher activity of ATP synthase in DS fibroblasts.
Valenti et al. [114] also observed a significant increase
of the level of complex III in the same type of fibro-
blasts. Remarkably, EGCG positive effects on the OX-
PHOS components were also obtained in Epstein–Barr
virus-immortalized lymphoblastoid DC cells lines
[114]. Conversely, other studies performed by Zheng
Dietary Polyphenols and Mitochondrial Function
and Ramirez [48], Valenti et al. [115] and Weng et al.
[116] indicated that EGCG has an inhibitory effect on
the mitochondrial respiratory chain. Moreover, it was
shown that high, supra-physiological doses of EGCG
are hepatotoxic [117], probably due to depletion of the
reduced form of glutathione [118, 119] and decreased
mΔΨ [118]. Similar observations were done by Kucera
et al. [111] in primary culture of rat hepatocytes show-
ing that EGCG can increase ROS production and trig-
ger mitochondrial depolarization at high concentra-
tions. In line, high concentrations of EGCG caused
OMM damage and induced mitochondrial uncoupling
in permeabilized hepatocytes [111]. The effect of
EGCG on in vitro and in vivo mitochondrial function
has been described recently by Oliveira et al. [73] and
Chowdhury et al. [120]. Extensive data on the EGCG
toxicity profile can be also found in other woks [121,
122].
4.1.4 Quercetin
Few examples on quercetin administration/treatment
for the improvement of mitochondrial function in dis-
orders have been found. However, some studies
pointed out indirect evidences of its beneficial effect on
mitochondrial bioenergetics. Joseph and Muralidhara
[123] have shown that quercetin oral supplementation
(together with fish oil) in a rotenone-induced rat model
of PD resulted in a neuroprotective effect, which is re-
lated to an increase of mitochondrial biogenesis, a
strategy that can compensate the deficit of energy and
counteract oxidative stress [104]. Another study has
shown that quercetin can protect brain mitochondria
from the side effects of oxaliplatin, a platinum-based
anticancer drug that induces mitochondrial dysfunction.
Oxaliplatin was shown to cause a decrease of brain mi-
tochondrial respiratory chain complexes (I, II, III) and
ATP synthase activity [124].
4.2. Cancer
Cancer is believed to be originated from different
multiple transformations in cells, which can be divided
in different hallmarks [125]. One of them regards
metabolic remodeling, in which mitochondria have an
important role. Multiple evidences (reviewed in [126,
127]) shows that mitochondrial metabolism is remod-
eled from energy production to biosynthesis of building
blocks for the cell, thus contributing to a fast cell pro-
liferation. The role of oxidative stress in cell transfor-
mation has also been established [127, 128], showing
that it is a driver of cancer progression by inducing ge-
netic alterations and by reprogramming metabolism. As
there is a general belief that naturally occurring poly-
Current Medicinal Chemistry, 2019, Vol. 26, No. 19 3385
phenols are linked to antioxidant effects and a lower
toxicity, some of those compounds are looked as a
promising candidates for the prevention or therapy of
different types of cancer.
4.2.1. Resveratrol
This dietary polyphenol has been used in a number
of clinical trials (ended and ongoing) in the US and EU
(https://clinicaltrials.gov/). Molecular mechanisms of
its chemopreventive and anticancer properties have
been recently summarized in two excellent papers [129,
130]. A rich-resveratrol diet has been found, for exam-
ple, to correlate with a significant decrease of the inci-
dence of skin and breast cancers and the progression of
lung adeno-carcinoma [131, 132]. When used together
with anticancer drugs, such as 5-fluorouracil (5-FLU)
[133], cisplatin [134] and arsenic trioxide [135], res-
veratrol potentiated their anticancer efficacy, che-
motherapeutics. Interestingly, resveratrol cytotoxic ef-
fects on breast cancer cells were modulated by SIRT1
and also involved mitochondrial complex I inhibition
has been shown by our group [136].
4.2.2. Curcumin
Taking into account its safety profile, curcumin was
approved by the Food and Drug Administration and the
Joint FAO/WHO Expert Committee on Food Additives
[137]. Although curcumin is known for its antioxidant
properties, it was observed that curcumin can increase
ROS production and mtDNA oxidative damage in
many tumor cell lines [138]. Karmakar et al. showed
that curcumin induced cytochrome c release and de-
creased cell viability, suggesting an induction of apop-
tosis via mitochondrial pathway [139] in brain glioblas-
toma cells [140]. In addition, curcumin cytotoxic ef-
fects on malignant breast cancer have been associated
with the induction of caspase-independent paraptosis
[141]. The overall data indicate that curcumin can in-
duce cancer cell death through different pathways. The
potential molecular mechanism of curcumin effects on
normal and cancer cells were already described by Tru-
jillo et al. [142] and Kumar et al. [143].
4.2.3. EGCG
EGCG is thought to prevent tumorigenesis by pro-
tecting cells from oxidative damage by a ROS scaveng-
ing mechanism. Moreover, EGCG anti-angiogenic, an-
tiproliferative, and/or pro-apoptotic properties have
also been described. A number of evidences recognized
EGCG chemopreventive and anticancer properties. For
example, Yamamoto et al. [144] showed that EGCG
protected normal salivary gland cells from the effect of
3386 Current Medicinal Chemistry, 2019, Vol. 26, No. 19
γ-irradiation or cis-platinum diamine dichloride
(CDDP)-based therapy. EGCG inhibit cancer invasion
and angiogenesis by inhibiting nicotine-induced over-
expression of matrix metalloproteinase (MMP) 9 with
suppression of NF-κΒ and AP-1 [145]. EGCG can also
inhibit the proliferation of cancer cells by activating
AMP-activated protein kinase (AMPK) and by inhibit-
ing the expression of cyclooxygenase-2 (COX-2), in
sensitized HT-29 colon cancer cells resistant to 5-FLU
[146]. Yamamoto et al. [147] measured EGCG effects
on non-tumor vs. tumor cells and observed in the latter
that EGCG induced oxidative stress in opposition to the
former, where reduced ROS levels were detected.
EGCG can promote tumor cell death and favor protec-
tion in normal cells, suggesting that different pathways
are activated, possibly also involving mitochondria
[147]. Interestingly and in contrast to the huge number
of evidences that demonstrate EGCG beneficial effects,
EGCG was shown to be toxic to normal mammary
epithelial cells [148]. Interesting data was found by
Tewes et al. [149], showing that green tea-drinkers
have a significant 2.7-fold increase in lung cancer risk.
Moreover, other studies also showed that EGCG can be
responsible for green tea-induced asthma [150], sug-
gesting that EGCG can induce histamine release in
green tea-sensitive patients [151]. Some of the effects
on cancer caused by EGCG, may also be related to epi-
genetics. Regulation of gene expression strongly de-
pends on the balance between acetylation and deacety-
lation of histones that are regulated by histone acetyl-
transferases (HATs) and histone deacetylases
(HDACs), respectively. It is well known that histone
modification processes differ significantly in normal
and tumor cells, and that may explain the selective anti-
tumor properties of EGCG. In fact, EGCG has been
found to be a HAT regulator [152, 153], showing in
fact a specific inhibitory effect on the majority of
HATs [154].
4.2.4. Quercetin
The most abundant flavonoid found in fruits and
vegetables, has been shown to have anticancer proper-
ties [155-158]. The properties of quercetin as a che-
mosensitizer have also been described by Chen et al.
[159]. In some studies, when quercetin is used in com-
bination with anticancer drugs, including cisplatin
[160] and doxorubicin, it increased their cytotoxicity
[161]. Quercetin can interact with ATP-Binding Cas-
sette (ABC) transporters enabling to overcome
multidrug resistance (MDR) in drug resistant tumor
cells. Quercetin was described to arrest cell cycle at S
phase in colorectal carcinoma [157], at G2/M phases in
Teixeira et al.
leukemia and breast carcinoma [162, 163] and at
G0/G1 phase in leukemia cells [163]. Srivastava et al.
[164] demonstrated that quercetin can cause tumor re-
gression by activating mitochondrial-dependent apop-
tosis. Quercetin was able to reduce breast adenocarci-
noma volume as well as increased the lifespan of
treated Swiss albino mice comparing to untreated con-
trol animals. Upregulation of p53 and BAX, cleavage
of caspase 3 and 9, PARP1 and MCL1, release of cyto-
chrome c and SMAC/DIABLO from mitochondria with
simultaneously observed downregulation of antiapop-
totic proteins like BCL2 and BCL-xL indicated the ac-
tivation of intrinsic mitochondrial cell death pathway
[164]. Interestingly, the authors excluded any role for
ROS on quercetin cytotoxic effects on tumor cells.
4.3. Neurodegenerative Diseases
Mitochondrial dysfunction is extensively described
to occur at an early stage in brain aging as well as in a
number of neurodegenerative diseases including Alz-
heimer Disease (AD), Parkinson Disease (PD) or
Huntington Disease (HD) [165-168]. Among other cel-
lular hallmarks, decreased mitochondrial membrane
potential and ATP levels, decreased respiratory capac-
ity as well as increased oxidative stress, mPTP opening
and programmed cell death have been observed [165,
166, 168-170]. Data accrued in the past decade has
convincingly demonstrated the health benefits of die-
tary polyphenols in several aspects related with the pa-
thology of neurodegenerative diseases (Fig. 5) [171].
4.3.1. Resveratrol
Neuroprotective properties of resveratrol have been
observed in several neurodegenerative models, such as
epilepsy, stroke, AD and PD through its ability to
modulate excitotoxicity, mitochondrial dysfunction,
oxidative stress and neuroinflammation [172-178].
Resveratrol was able to protect animal models from
neurological, and related cardiovascular damage, in-
duced by stroke and brain trauma, through multiple
mechanisms, which include the decrease of oxidative
damage and apoptosis and the regulation of mitochon-
drial function [179]. Several studies have confirmed the
neuroprotective and anti-amyloidogenic effects of res-
veratrol in both in vitro and in vivo models of AD in
response to its capacity to attenuate oxidative stress
injury and reverse cognitive deficits [171]. Resveratrol
was found to inhibit the formation and aggregation of
amyloid beta (Aβ) fibrils, as well as their destabiliza-
tion, reducing in that way the neurodegeneration in the
hippocampus and attenuating intracellular ROS accu-
mulation [180, 181]. Resveratrol administration has
Dietary Polyphenols and Mitochondrial Function
also protected a rodent PD model from 1-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced
motor coordination impairment, hydroxyl radical over-
loading, and neuronal loss [182]. Resveratrol has also
shown beneficial effects in a 6-hydroxydopamine-
induced PD rat model [183]. Moreover, resveratrol par-
tially rescued the mitochondrial respiratory capacities
in Parkin-mutated fibroblasts possibly by sustaining
and increasing mitochondrial function, throughout the
up-regulation of key regulatory enzymes involved in
cellular and mitochondrial metabolism [184]. Resvera-
trol also exerted positive effects in a SOD1G93A
model of amyotrophic lateral sclerosis (ALS) through
the preservation of both lower and upper functions in
motor neurons, which were translated into a significant
delay of disease onset and extended animal survival
[185].
4.3.2. Curcumin
Several in vivo studies have shown that curcumin at-
tenuates oxidative stress in several models in which
ROS generation was triggered by one or more factors
such as the pathological state, the use of drugs, chemi-
cals, and diet [142]. In in vitro and in vivo models of
PD curcumin was found to play an important role in the
prevention of dopaminergic neuron loss. In a rotenone-
induced Drosophila and cellular model of PD, curcu-
min improved PD-like symptoms and prevented apop-
tosis, respectively [186, 187]. In vitro and in vivo stud-
ies in AD models have shown that curcumin can inhibit
the formation of Aβ fibrils, namely Aβ40 and Aβ42
[188]. Moreover, in the brain of an Alzheimer’s trans-
genic mouse model (Tg2576), curcumin suppressed
inflammation and oxidative damage [189]. Although
such effects were primarily attributed to curcumin free
radical scavenging properties, curcumin also chelates
redox-active metal ions, such as Cu2+ and Fe2+ [171,
190]. Moreover, curcumin can also upregulate Nrf-2
dependent genes that encode for several cytoprotective
proteins and antioxidant enzymes [191]. Several ex-
periments have also reported curcumin beneficial ef-
fects in HD [192, 193]. In this particular case, the
activation of phosphatidylinositol 3-kinase (PI3K)/Akt
pathway and subsequent Nfr2 nuclear translocation was
shown to play a crucial role in curcumin-mediated neu-
ronal survival [194-197]. Curcumin also showed neu-
roprotective properties in cerebral ischemia reperfusion
(I/R) injury through its capability to reverse the depres-
sion of mitochondrial biogenesis (NFR-1, TFAM), mi-
tochondrial number and mitochondrial protein uncou-
pling protein (UCP) 2 [198].
Current Medicinal Chemistry, 2019, Vol. 26, No. 19 3387
4.3.3. EGCG
EGCG has been shown noteworthy antioxidant and
neuroprotective effects in preclinical models of neu-
rodegenerative diseases, especially in AD and PD [199-
201]. In general, neurodegenerative diseases are usu-
ally accompanied by fuel restrictions in neurons and
mitochondrial impairment. EGCG has been shown to
target energy metabolism in several cell types, mainly
as an agonist of AMPK, the main energy sensor in the
cell [202, 203]. EGCG is an attractive drug candidate
for AD pharmacotherapy, due to its beneficial effects
on age-related cognitive deficits and memory loss
[204]. EGCG showed accumulation in mitochondria
and displayed protective effects against mitochondrial
oxidative stress in rat neurons [205], restoring mΔΨ,
mitochondrial function as well as ATP synthesis.
Moreover, EGCG was reported to reduce Aβ genera-
tion in both N2a-overexpressing human Swedish mu-
tant amyloid precursor protein (APP) and in primary
neurons derived from Tg2576 rats [206]. EGCG bene-
ficial effects in PD, evaluated in in vitro and animal
models, were recently reviewed. It was proposed that
EGCG not only has antioxidant and anti-chelating
properties but can also directly interfere with the ag-
gregation of the α-synuclein protein and modulate in-
tracellular signaling pathways [207]. EGCG also
showed neuroprotective properties in brain ischemia.
The effects were found to be mediated by diverse
mechanisms, namely by decreasing the activity of the
inducible NOS (iNOS) expression, by reducing per-
oxynitrite formation, by protecting mitochondrial com-
plexes activity and organelle integrity and by ferric iron
chelation [208]. EGCG also reversed nitropropionic
acid (3-NP)-induced histological and behavioral altera-
tions, oxidative damage, and mitochondrial dysfunction
[209], probably through NOS inhibition. To note that
the 3-NP induced HD model replicates most of the
clinical and pathophysiological hallmarks of HD, in-
cluding spontaneous choreiform and dystonic move-
ments, frontal-type cognitive deficits, and progressive
striatal neuronal degeneration [210].
4.3.4. Quercetin
Quercetin has been reported to attenuate behavioral
alterations and cognitive impairment in PD [211] and
in chronic cerebral ischemia models [212]. In an ani-
mal model of aluminum-induced toxicity, which has
been linked etiologically and epidemiologically to sev-
eral neurological disorders, including AD [213], PD
[214] and ALS [215], quercetin supplementation was
found to reduce oxidative stress by decreasing ROS
3388 Current Medicinal Chemistry, 2019, Vol. 26, No. 19
production and increasing antioxidant levels, that at the
end decrease lipid peroxidation and protein oxidation
[216, 217]. Moreover, quercetin prevented mitochon-
drial dysfunction, oxidative stress along with motor
deficits in 3-NP-induced HD [218]. Regarding AD,
quercetin was found to decrease APP maturation
through the regulation of APP processing [219] and to
prevent Aβ-induced neurotoxicity in primary neuronal
cells [220], which in turn reduced Aβ-induced mito-
chondrial dysfunction and improved cognitive impair-
ment [221]. Although the beneficial effects of quercetin
in brain are primarily attributed to its antioxidant ac-
tion, quercetin was shown to improve mitochondrial
function by increasing mitochondrial biogenesis and
thus improving mitochondrial capacity [222].
4.4. Hepatic Diseases
In Europe and North America, liver diseases repre-
sent a major medical problem, being alcohol abuse and
over-nutrition the major causes of liver pathological
conditions Non-alcoholic fatty liver disease (NAFLD)
is considered one of the manifestations of the metabolic
syndrome, with an estimated prevalence in the general
population of Western countries between 9% and 30%.
NAFLD comprises a broad spectrum of hepatic pa-
thologies including simple steatosis, nonalcoholic stea-
tohepatitis (NASH), fibrosis, and cirrhosis, which are
ultimately capable of inducing hepatocellular carci-
noma [223, 224]. Hepatotoxicity is also described as a
main consequence of drug-induced organ injury. Clini-
cally, drug-induced liver injury is the most frequent
cause of acute liver failure [225]. The main mecha-
nisms of drug-induced liver damage are mitochondrial
dysfunction and alteration of lipid metabolism, which
can be caused by the drug itself and/or by its reactive
metabolites. Moreover, unlike other major causes of
mortality, liver disease rates are increasing rather than
declining [226]. Due to their pleotropic properties, the
use of natural products in the prevention and treatment
of liver diseases [227-229] or protection of liver against
various insults [230-232] has gained considerable trac-
tion (Fig. 5).
4.4.1. Resveratrol
Resveratrol has been shown to protect liver damage
caused by hepatic ischemia-reperfusion [233, 234],
ethanol toxicity [235], high fat diet [236] and hepato-
toxic agents such as acetaminophen [237, 238] and
carbon tetrachloride (CCl4) [239]. Moreover, resvera-
trol was effective for the treatment of pancreatitis in
Teixeira et al.
rats [240, 241]. The mechanisms that have been pro-
posed to explain the effects include antioxidant protec-
tion, up-regulation of antioxidant enzymes, modulation
of inflammatory responses, and induction of mitochon-
drial biogenesis [237, 238, 242, 243]. Resveratrol was
shown to activate AMPK through its ability to activate
SIRT1, which acts as a metabolic regulatory by sensing
NAD+ levels and also as an upstream regulator of
AMPK [244]. Resveratrol was also shown to up-
regulate hepatic UCP2 expression and to prevent the
development of NAFLD in a high-fat diet-treated ro-
dent model, which is characterized by hepatic accumu-
lation of triglyceride without concomitant inflamma-
tion. Such increased UCP2-derived mitochondrial un-
coupling dissipate the excess energy as heat at the ex-
pense of ATP synthesis and OXPHOS [245].
4.4.2. Curcumin
Numerous in vitro studies suggested that curcumin
antioxidant and anti-inflammatory properties may ac-
count for its protective effect in chronic liver disease.
Experiments demonstrated that curcumin plays a major
role in hepatocytes protection by inhibiting the produc-
tion of NO and tumor necrosis factor alpha (TNF-α)
lipopolysaccharide (LPS)-activated Kupffer cells [246].
Kaur et al. [247] reported that in the liver homogenates
from LPS-challenged rats, curcumin supplementation
decreased lipid peroxidation and increased GSH and
SOD levels. In a rat model of thioacetamide-induced
hepatotoxicity, curcumin was found to improve animal
survival rates through inhibition of the nuclear binding
of NF-κΒ and the iNOS protein expression [248].
Moreover, curcumin treatment attenuated liver steatosis
induced by TNF-α injection in mice, which is reflected
by a decrease of oxidative stress, neutrophils infiltra-
tion, and improved histopathology markers [249]. In a
male rat model of alcohol-induced and high-fat diet
liver injury, curcumin decreased histopathological
changes in the liver and the hepatic tissue levels of cho-
lesterol, triglycerides, and free fatty acids [250]. Rami-
rez-Tortosa et al. [251] showed that curcumin supple-
mentation to experimental rabbits with high-fat-
induced NASH lowers the disease grade and up-
regulated mitochondrial antioxidants with respect to
control animals. Kuo et al. [252] demonstrated that
curcumin treatment decreased inflammatory response
in adipose tissue, liver and blood of obese mice. The
decreased inflammation in curcumin-treated mice was
related with the observed beneficial effects on mito-
chondrial dysfunction associated with obesity-induced
liver steatosis.
Dietary Polyphenols and Mitochondrial Function
4.4.3. EGCG
EGCG has been reported to have beneficial effects
in many animal models of liver disease such as in I/R
injury, fatty liver and alcoholic liver damage [253-
256]. Administration of EGCG was effective in attenu-
ating bile duct ligation-induced liver injury and fibrosis
through a decrease ROS-induced hepatocyte cell death
and down-regulation of pro-fibrotic gene expression in
stellate cells [257]. EGCG also restored Mn-SOD,
GPx, complex I, complex II and complex IV enzyme
activities [73]. In other study using a NAFLD mice
model, EGCG administration improved hepatic mor-
phology and function, reduced body weight, and allevi-
ated hyperlipidemia, hyperglycemia and insulin resis-
tance [258]. The protective effect of EGCG was pro-
posed to be related with its ability to modulate mito-
chondrial oxidative/nitrative stress, NF-κΒ activation
and inflammatory processes [257].
4.4.4. Quercetin
Quercetin has been reported to have broad bioactiv-
ity profile, such as antioxidative and hypolipidemic
properties [77, 259], as well as hepatoprotective prop-
erties in rats chronically treated with CCl4 [260]. In
vitro [261] and in vivo [262, 263] data confirmed quer-
cetin hepatoprotective effects against ethanol hepato-
toxicity, by counteracting oxidative stress, avoiding
dyslipidemia and mitochondrial damage [264]. Moreo-
ver, quercetin prevented NaAsO2-induced liver fibro-
genesis, which was confirmed by histopathological and
histochemical analysis [265]. During experiments per-
formed in a high-fat diet mice model, quercetin was
able to decrease obesity, and reduce body and liver
weights, as well as the amount of white adipose tissue.
Quercetin also reduced high-fat diet-induced increased
serum lipids and thiobarbituric acid-reactive substances
(TBARS) [266]. Mechanistically, quercetin was pro-
posed to rapidly activate Nrf2 and consequently in-
crease the antioxidant defense system in HepG2 cells
[267].
4.5. Cardiovascular Diseases
Cardiovascular diseases (CVD) such as coronary ar-
tery disease, hypertension, congestive heart failure and
stroke are leading causes of death and disability in the
developed world [268]. Heart failure is characterized
by a profound myocardial dysfunction resulting in the
inability of the cardiac pump to meet the requirements
of the body [269, 270]. In diabetic patients, cardiovas-
cular complications account for the morbidity and mor-
Current Medicinal Chemistry, 2019, Vol. 26, No. 19 3389
tality. The association between cardiac dysfunction and
diabetes is related with distinct diabetes-induced car-
diac structural, metabolic and functional changes [271].
In general, oxidative stress-related mitochondrial dys-
function [272] and endothelial cell dysfunction [273]
are considered to be important pathogenic factors in
CVD. Consequently, the consumption of dietary poly-
phenols has been associated with a reduced incidence
of risk factors for CVD (Fig. 5) [274].
4.5.1. Resveratrol
The cardioprotective effects of resveratrol have
been attributed to its antioxidant and anti-inflammatory
properties [275]. Multiple evidence from in vitro, ex
vivo, and animal studies indicate that resveratrol exerts
cardiovascular protection by reducing oxidative stress
[276]. Resveratrol reverted endothelial dysfunction in
human endothelial cells stimulated with mimetic car-
diovascular risk factors, such as cigarette smoke extract
and H2O2 [277]. Moreover, in vivo experiments per-
formed on rat aortas fed with high-fat/sucrose diet
(HFS) showed that rats treated for 3 months with res-
veratrol were better protected against the effect of HFS
[278]. In an experimental mice model, resveratrol
treatment decreased doxorubicin-induced cardiomyo-
cyte apoptosis and cardiotoxicity and preserved cardiac
function [279]. Resveratrol exhibited beneficial effects
in hypertension-induced heart failure by increasing
survival, reducing body wasting and improving cardiac
and endothelial function. The major metabolic effect of
resveratrol in both cardiac and skeletal muscles was to
restore the expression of peroxisome proliferator-
activated receptor alpha (PPARα), to attenuate the
down-regulation of PGC-1α transcription cascade and
decrease of mitochondrial lipid oxidation [280]. Differ-
ent studies demonstrated that resveratrol can decrease
oxidative stress in diabetic cardiomyopathy, an effect
that in part is related to the inhibition of ROS produc-
tion and increment of antioxidant capacity, which
jointly contribute to increase cardiac function [281-
283]. In several forms of heart failure, such as in dia-
betic cardiomyopathy, the cardioprotective effect of
resveratrol is related with the activation of SIRT1
and/or SIRT3 [284]. Resveratrol has also been shown
to protect against ischemia events by modulating exci-
totoxicity, mitochondrial function, blood vessel integ-
rity, and NO signaling [285-287]. Interestingly SIRT1
was found to be required to mediate ischemic protec-
tion effects [288, 289]. Myocardial reperfusion injury
in mice models was also shown to be prevented by res-
veratrol, in a mechanism involving mPTP closure and
decreased ROS production [290].
3390 Current Medicinal Chemistry, 2019, Vol. 26, No. 19
4.5.2. Curcumin
In vitro studies have demonstrated curcumin re-
markable protective effects against anoxia-
reoxygenation-induced oxidative damage of rat heart
mitochondria [291]. Curcumin antioxidant properties
were linked to the observed cardioprotective effect
against catecholamine-induced cardiotoxicity [292,
293]. Moreover, pre-treatment of isolated rat hearts
with curcumin (200 mg/kg by 7 days) decreased I/R-
induced mechanical injury [294]. The decrease of oxi-
dative stress and inflammation through the inhibition of
NF-κΒ activation, and consequently the attenuation of
mitochondrial dysfunction, played an important role in
cardiac cells protection against I/R injury [293, 294].
Curcumin was also shown to prevent heart failure in
rats by inhibiting p300 histone acetyltransferase activ-
ity [295] and by decreasing the probability of mPTP
opening [293, 296]; as consequence curcumin pre-
served mitochondrial function and prevented apoptosis.
4.5.3. EGCG
EGCG received much attention as a protective agent
against CVD [297-299]. For instance, EGCG protected
mitochondria from damage during isoproterenol-
induced cardiotoxicity due to its antioxidant properties
[300]. Moreover, EGCG was shown to attenuate pres-
sure overload-induced left ventricular cardiac hyper-
trophy in rats through: (i) inhibition of the activity and
protein expression of antioxidant enzymes, resulting in
decreased ROS and lipid peroxidation levels; (ii) inhi-
bition of MAPK activation, DNA binding activity of
AP-1 and NF-κΒ and expression of MMP-9; and (iii)
prevention of mtDNA damage and dysfunction [301].
In a myocardial I/R injury animal model, perfusion of
EGCG during ischemia significantly reduced infarct
size after reperfusion, with ATP-sensitive K+ channels
in mitochondria playing a crucial role in EGCG-
induced cardioprotection [302]. Additionally, the inhi-
bition of mPTP opening, by preventing the [Ca2+]m
overload-induced apoptosis, appeared also to be impor-
tant for the observed protective effects in I/R hearts
[299]. In addition, experiments with a tea supplement
given to rabbits or rats with an atherogenic diet showed
a reduction of serum lipoproteins and incidence of
atherosclerosis [303]. Green tea extracts were also
shown to lower plasma cholesterol and triglyceride lev-
els in rats [304].
4.5.4. Quercetin
Quercetin was shown to increase the resistance of
low-density lipoproteins to oxidation without affecting
lipoprotein profiles or platelet aggregation, which are
Teixeira et al.
well-known risk factors for heart disease [305, 306].
Punithavathi et al. [307] showed that pretreatment with
quercetin and α–tocopherol had protective effects on
heart mitochondria from isoproterenol-treated rats, be-
ing the overall protective effects due to their ability to
scavenge free radicals. Quercetin also decreased the
extension of mitochondrial damage and lipid peroxida-
tion, restored the antioxidant defense system, and nor-
malized the TCA cycle, respiratory chain enzymes,
Ca2+ fluxes and ATP levels in isoproterenol-treated
myocardial infarcted rats [307]. Brookes et al. [308]
observed that a daily oral intake of quercetin at doses
equivalent to consumption of drinking 1–2 glasses of
red wine can significantly protect the heart against I/R
injury. The observed cardioprotective effect is related
with improvement of post-I/R mitochondrial function
and Mn-SOD activity [308].
CONCLUSION
In this review, the health benefits of four dietary
polyphenols – resveratrol, curcumin, EGCG and quer-
cetin-were described in the context of pathologies in
which mitochondrial dysfunction has special relevance.
Table 1 summarizes the pros and cons of the four poly-
phenols described in this review. Despite what has
been reviewed in this work, it is clear that the positive
effects of the four polyphenols can go beyond direct
mitochondrial effects. In general, in vitro and in vivo
studies suggested that the beneficial effects of the
aforementioned polyphenols arise from, but are not
limited to, the ability to modulate oxidative stress, en-
zymatic activity, gene expression and signal transduc-
tion pathways relevant for the disease progression.
However, despite the supportive epidemiologic and
animal data, the use of polyphenols on disease preven-
tion or therapy has been failing in clinical trials. Their
therapeutic efficacy evaluation may be restrained by
several speculative explanations, such as the inappro-
priate dosages and/or durations of the tests, inadequate
test subjects (e.g. patients in an advanced stage of a
disease in which the damages are irreversible) and er-
rors on the study design [309, 310]. Furthermore, the
pharmacologically active doses may not be attained
due to polyphenols pharmacokinetic constrains which
limit their bioavailability. Polyphenols are, in general,
poorly absorbed and rapidly metabolized and excreted
[311]. To overcome the pharmacokinetic barriers, and
taking into account the central role of mitochondria in
health and pathology, the design of innovative
mitochondriotropic compounds is an emerging area.
This class of compounds has the ability to easily
Dietary Polyphenols and Mitochondrial Function Current Medicinal Chemistry, 2019, Vol. 26, No. 19 3391

Table 1. Summary of the polyphenols described in the text and their positive and negative effects.

Positive Effect
Polyphenol References
Negative Effect

1) Direct scavenging of ROS. [47]

2) Induction of apoptosis in several malignant cell lines. [49, 50]
3) Decreases oxidative stress in the case of mitochondrial complex I deficiency. [101]
4) Restores oxygen consumption in complex I-deficient patient cell lines. [101, 102]
5) Potentiates the anticancer efficacy of chemotherapeutics. [133, 134, 135]
6) Significant decreases in the incidence of skin and breast cancers and the progression of [131, 132]
lung adeno carcinoma.
7) Neuroprotective properties in several neurodegenerative models. [172-178]
8) Protects animal models from neurological and related cardiovascular damage. [179]
9) Anti-amyloidogenic effect in both in vitro and in vivo models of AD. [171]
10) Inhibits the formation and extension of amyloid beta (Aβ) fibrils. [180, 181]
11) Beneficial effects in a 6-hydroxydopamine-induced PD rat model. [183]
Resveratrol 12) Positive effects in the SOD1G93A model of amyotrophic lateral sclerosis (ALS). [185]
13) Protects liver damage caused by hepatic ischemia-reperfusion. [233, 234]
14) Protects liver damage caused by ethanol toxicity. [235]
15) Protects liver damage caused by high fat diet. [236]
16) Protects liver damage caused by hepatotoxic agents. [237-239]
17) Protects against pancreatitis in rats. [240, 241]
18) Cardioprotective effect. [275, 278, 279]
19) Decreases oxidative stress in diabetic cardiomyopathy. [281-283]
20) Prevents mPTP opening in myocardial reperfusion injury. [290]
1) Inhibition of complexes I and III of the OXPHOS. [45, 46]
2) Inhibition of F1FO-ATP synthase/ATPase. [46]
3) Decreases ATP production, may cause bionergetic collapse in individuals with ATP [48]
synthesis deficits. [88]
1) Anti proliferative and antineoplastic effect. [54-60]
2) Induction of apoptosis in human hepatoblastoma , leukemia and glioblastoma cells. [61, 62, 138, 140]
3) Anti-inflammatory effect. [66, 252]
4) Anti-obesity effect. [67, 68]
5) Anti-aging. [69]
6) Positive effects when tested for in AD patients. [98, 99]
7) Restores the activity of complexes I, II and III, which were affected by chronic admini- [108]
stration of D-galactose.
8) Augments ATP level, in brain of diabetic rats. [109]
9) Protects the mitochondrial respiratory chain against the pro-oxidative effect of hy- [106]
droxynonenal,.
10) Increases ROS production and mtDNA oxidative damage in many tumor cell lines. [138]
Curcumin 11) Prevention of dopaminergic neuron loss in in vitro and in vivo models of PD. [186, 187]
12) Inhibits the formation of Aβ fibrils. [188]
13) Beneficial effect in HD. [192, 193]
14) Neuroprotective properties in cerebral ischemia reperfusion (I/R) injury. [198]
15) Protective effect in chronic liver disease. [246, 247]
16) Attenuates liver steatosis induced by TNF-α in mice. [249]
17) Decreases hepatic tissue levels of cholesterol, triglycerides, and free fatty acids. [250]
18) Protective effect against anoxia-reoxygenation-induced oxidative damage of rat heart [291]
mitochondria.
19) Cardioprotective effect against catecholamine-induced cardiotoxicity. [292, 293]
20) Reduces I/R-induced heart injury. [293, 294]
1) Inhibition of ATPase activity of complex V [48]
1) Antioxidant properties. [74, 111]
2) Positive effects on OXPHOPS, in fibroblasts of Down's syndrome (DS) individuals [112-114]
with impaired mitochondrial complex I and ATP synthase.
EGCG
3) Prevents tumorigenesis by protecting cells from oxidative damage by a ROS. [144]
4) Inhibits cancer invasion and angiogenesis. [145]
5) Inhibits the proliferation of cancer cells. [146]

(Table 1) contd….
3392 Current Medicinal Chemistry, 2019, Vol. 26, No. 19 Teixeira et al.

Positive Effect
Polyphenol References
Negative Effect

6) Beneficial effects in many animal models of liver disease such as in I/R injury, fatty [253-256]
liver and alcoholic liver damage.
7) Prevents mitochondria in the case of induced cardiotoxicity. [300]
8) EGCG-induced cardioprotection. [302]
9) Inhibits mPTP opening in I/R hearts [299]
1) Inhibits ATPase activity of complex V. [48]
2) Inhibition of the mitochondrial respiratory chain. [116]
EGCG 3) Supra-physiological doses of EGCG are hepatotoxic. [117, 118, 119]
4) Supra-physiological doses of EGCG increase ROS production and trigger mito- [111]
chondrial depolarization in primary culture of rat hepatocytes.
5) Toxic to normal mammary epithelial cells. [148]
6) Suspect for green tea-induced asthma. [149]
7) Neuroprotective effects in preclinical models of AD and PD. [199-201]
8) Beneficial effects on age-related cognitive deficits and memory loss. [204]
9) Reduces Aβ generation. [206]
1) Potent scavenger of ROS and NOS. [77]
2) Neuroprotection. [76, 81, 123]
3) Inhibits (5 μM) mPTP opening. [92]
4) Anticancer properties. [155, 156, 157, 158]
5) Chemosensitizer. [159, 160, 161]
6) Attenuates behavioral alterations and cognitive impairment in PD and chronic cerebral [211]
ischemia models.
7) Reduces oxidative stress . [216, 217]
8) Prevents Aβ-induced neurotoxicity in primary neuronal cells. [220]
Quercetin 9) Hypolipidemic properties. [259]
10) Hepatoprotective properties. [260]
11) Prevents liver fibrogenesis. [265]
12) Increases the resistance of low-density lipoproteins to oxidation without affecting [305, 306]
lipoprotein profiles or platelet aggregation.
13) Significantly protects the heart against I/R injury. [308]
1) Inhibits ATPase activity of complex V. [48]
2) Induces (> 40 μM) mPTP opening. [92]
3) Pro-oxidant mechanism for mPTP opening. [92, 93]

penetrate into the cell and rapidly and extensively ac-
cumulate into the mitochondria, driven by the mΔΨ,
[312]. Thus, the development of innovative mitochon-
drial-targeted polyphenols may be an effective thera-
peutic approach with promising impact on medicine.
CONSENT FOR PUBLICATION
Not applicable.
(UMO-2014/15/B/NZ1/00490) for MRW and AKW as
well as by the Internal Projects of The Children’s Me-
morial Health Institute No S125/2012 and S141/2014
for MRW and AKW.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial
or otherwise.

FUNDING ACKNOWLEDGEMENTS
This work was funded by FEDER funds through the Declared none.
Operational Programme Competitiveness Factors -
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