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Current Medicinal Chemistry, 2015, 22, ????-???? 1

Mitochondria-Mediated Oxidative Stress: Old Target for New Drugs

Alex Lyakhovich1,2,* and Dmitri Graifer3

1
International Clinical Research Center-ICRC, St. Annes Hospital, Masaryk University,
Brno, Czech Republic; 2Novosibirsk Institute Molecular Biology and Biophysics, Russia;
3
Novosibirsk State University, Novosibirsk, 630090, Russia Please provide
corresponding author(s)
photograph
Abstract: Oxidative stress, one of the crucial factors of genomic instability, is involved in size should be 4" x 4" inches

many illnesses - from DNA damage and repair (DDR) related diseases to neurological ab-
normalities and cancer. Patients with defective DDR pathways display high level of cancer
predisposition and at the same time - reveal hydrocephalia, dementias and even diabetes
mellitus - all representing common hallmarks of mitochondria-related disorders. Since mito-
chondria are responsible both for the cell energetic metabolism and for reactive oxygen/nitrogen species
(RO/NS) formation, mitochondrial dysfunction (MDF) play a pivotal role in the above disorders. Not surpris-
ingly, RO/NS are considered to be a primary target for a large spectrum of compounds aiming to eliminate
these adverse species or, in contrary, enhance their presence in order to amplify cellular death pathways. Yet,
only few chemicals have received medical appreciation mainly because of their questionable therapeutic val-
ues in healthy states. As a result, recent efforts have been focused on finding the drugs that improve mito-
chondrial functions or chemoprevent MDF rather than being applied as RO/NS scavengers. This review ad-
dresses the most recent progress in the development and application of such chemicals and outlines some fu-
ture perspectives.
Keywords: Apoptosis, chemoprevention, mitochondria, mitophagy, oxidative stress, RNS, ROS.

INTRODUCTION As overproduction of RO/NS may cause MDF and

The imbalance between ROS generation and detoxi-
fication, known as oxidative stress (OS), is thought to
be involved in a variety of disorders - from DDR re-
lated diseases to neurological abnormalities and cancer
[1]. Patients with defective DDR pathways display high
level of cancer predisposition and at the same time -
reveal some common hallmarks of mitochondria-
related disorders (MRD), including hydrocephaly, de-
mentia and even diabetes mellitus [2]. Since mitochon-
dria are responsible for both the cellular energy me-
tabolism and RO/NS formation, there seems to be a
connection between the above diseases and mitochon-
drial dysfunction [3].
Oxidative phosphorylation (OxPhos) is a major
metabolic pathway for the oxidation of nutrients to re-
form ATP in mitochondria which generate a mitochon-
drial membrane proton gradient (P) and transfer elec-
trons through mitochondrial complexes I-V [4].
*Address correspondence to this author at the International Clinical
Research Center-ICRC, St. Annes Hospital, Masaryk University,
Brno, Czech Republic; Tel/Fax: +44 2895 81 7215;
E-mails: lyakhovich@gmail.com and alex.lyakhovich@mail.muni.cz
contribute to a plethora of disorders with diverse clini-
cal phenotypes, mitochondria-mediated OS has become
an obvious therapeutic target in medical research [5].
Since early 70s, when the biological importance of mi-
tochondria-mediated OS has attracted a great interest,
more than 12,000 papers have been published, half of
them during the last five years. This review will focus
predominantly on the drugs and their modes of action
directed against mitochondria-mediated RO/NS path-
ways with proven track records of pharmacological
activities and at least ten published references.
2. MITOCHONDRIA-MEDIATED OS AND CON-
SEQUENCES
In mammalian systems RO/NS presumably include
free radicals (OH, RO, ROO, NO, hydroxyl,
alkoxyl, peroxyl and nitroxyl) and superoxide (O2),
as well as hydrogen or organic peroxides (H2 O2 ,
RO2H). In healthy state, RO/NS are mainly generated
by OxPhos in mitochondria through mitochondrial
complexes I and III (Fig. 1). For complex I within in-
tact mitochondria, only small amounts of O2 are pro-
duced depending on NADH/NAD+ ratio, which is rela-

0929-8673/15 $58.00+.00 2015 Bentham Science Publishers

2 Current Medicinal Chemistry, 2015, Vol. 22, No. 1
tively low [6]. At the same time, when the p is high, a
reduced set of coenzymes Q (CoQ) leads to reverse
electron transport (RET) causing a high flux of O2
from the complex I [7]. In complex III, ROS are gener-
ated by proton gradient between cytochrome b, c1,
ubiquinone and iron-sulfur protein complexes [8]. In
turn, nitric oxide (NO) is generated by the nitric (NOS)
and mitochondrial NO synthase (mtNOS) enzymes in
three major isoforms: inducible NOS (iNOS), neuronal
NOS (nNOS), and endothelial NOS (eNOS) [9]. In
pathological conditions, high level of RO/NS is a
common hallmark and can be mitochondria dependent
(ischemia, loss of cytochrome c, low ATP demand and
consequent low respiration rate, diabetes, DNA dam-
age, mutations), independent or indirect (cancers, tissue
injuries, inflammatory events) [10-11]. When mito-
chondria are involved, the NADH/NAD+ ratio is in-
creased which results in O2 formation [12-13]. Mito-
chondrial ROS production is also reported to increase
under hypoxic conditions (1- 3% of oxygen) [14]. In
excess amounts, the RO/NS may react with most of
cellular components which leads to oxidation of pro-
teins (thiol groups, amino groups and methionine), lip-
ids and nucleotides thus causing detrimental conse-
quences [15-16]. RO/NS are thought to trigger or to be
associated with a variety of disorders including rheu-
matoid arthritis, Alzheimer's disease, Parkinson's dis-
ease [16-20]. Role of RO/NS is well validated for car-
diovascular diseases, where oxidation of low density
lipoprotein may result in atherosclerosis [21]. Impor-
tantly, being the main source of RO/NS generation,
mitochondria are also their primary and the most sus-
ceptible target. This may evoke a secondary wave of
OS generated by damaged mitochondria followed by
formation of extra RO/NS or by inhibition of detoxify-
ing enzymes and produce more RO/NS flux thus form-
ing a vicious cycle [22]. In healthy conditions several
antioxidant enzymes such as Mn-, Cu-, Zn-containing
superoxide dismutases (SODs), glutathione peroxidase,
glutathione reductase (GPx), glutathione S-transferases
(GSTs), catalase, etc. protect DNA from OS [23,24].
Polymorphisms in these enzymes have been reported to
be associated with DNA damage, and risk of MDF
[25,26]. The role of MDF therefore is more critical for
pathological conditions as, for example, in DDR re-
lated diseases where defects in DDR machinery can
damage mitochondria and impair mitochondrial detoxi-
fying apparatus [27]. During MDF stipulated by
mtDNA mutations, lack of expression of detoxifying
enzymes and age-related factors, high levels of RO/NS
can be accumulated [28,29]. If not detoxified com-
pletely, these reactive products may damage mitochon-
Lyakhovich and Graifer
dria and cells by several pathways leading to apoptosis
(Fig. 1). All these facts make mitochondria-mediated
RO/NS an appealing pharmacological target.
Fig. (1). Two groups of chemicals targeting mitochondria-
mediated OS. Oxidative stress is the imbalance between gen-
eration and detoxification of oxidative and nitrogen species
(RO/NS) that is presumably mediated by mitochondria, the
main source and primarily target of RO/NS. If not detoxified
completely, excess of the RO/NS may lead to oxidation of
DNAs and proteins and elicit inflammation, cancer, auto-
phagy or apoptosis. Medically applied substances that affect
mitochondria-mediated RO/NS can be divided into two an-
tagonist groups (i) cytotoxic compounds aiming to amplify
RO/NS-mediated cell death pathways or sensitize certain
drugs that destroy mitochondria by overproduction of RO/NS
(death signaling inducers and mitochondria permeabilizers)
and (ii) chemicals aiming to eliminate RO/NS either as non-
specific scavengers or bioenergetic enhancers that facilitate
mitochondrial functions by decreasing RO/NS (antioxidants
and bioenergetic enhancers). Dotted arrow lines highlight
shared properties for different groups of drugs.
Medically applied substances that affect mitochon-
dria-mediated RO/NS can be divided into two antago-
nist groups (i) cytotoxic compounds aiming to amplify
RO/NS-mediated cell death pathways and/or sensitize
certain drugs that destroy mitochondria by overproduc-
tion of RO/NS and (ii) chemicals aiming to eliminate
RO/NS either as non- specific scavengers or bioener-
getic enhancers that facilitate mitochondrial functions
by decreasing RO/NS (Fig. 1). Accordingly, we will
consider each group individually, focusing on effec-
tiveness and therapeutic values of certain drugs as well
as side effects and potential applicability (Table 1).
3. DRUGS INDUCING CELL DEATH SIGNAL-
ING PATHWAYS
Induction of apoptosis or specific autophagy (mito-
phagy) through mitochondria- mediated OS represents
Drugs Targeting Oxidative Stress in Mitochondria Current Medicinal Chemistry, 2015, Vol. 22, No. 1 3

Table 1. Drugs targeting mitochondria-mediated oxidative stress. Drugs targeting mitochondria-mediated ROS can be
either cytotoxic compounds aiming promoting cell death pathways or chemicals aiming to eliminate ROS to
enhance mitochondrial functions. In bold are depicted the most feasible chemicals selected in accordance to
section 5 principles.

Type Compounds Mode of action Related Diseases References

Alpha-tocopheryl suc- Interacts with UbQ-binding site, inhibits SDH

Cancer [40-43]
Pro-apoptotic cell death inducers

cinate activity of complex II yielding ROS

BMD188 ROS-dependent activation of caspase-3 Prostate cancer [44,45]
Ionidamine Activation of caspase-9, -3, Akt/mTOR Leukemia [46,47]
Inhibition of Bcl-2 members, ROS increase, Multiple myeloma
Gossypol [48-51]
Activation of caspase-3, Cyt c release Burkitt lymphoma
PUFAs Target ROS-mediated Akt-mTOR Prostate cancer [52-54]
Etomoxir Blocks -oxidation of FAs, induces ROS Leukemia, glioma, Colon cancer [55-58]
Target thioredoxin reductase, increase ROS,
Trx inhibitors Chronic myeloid leukemia [59-63]
activate caspase 3
ESOM Inhibit proton pumps Melanoma [67-69]
Inducers of mitophagy and permeabilizers

Dichloroacetate Inhibit Hsp70 expression and mTOR Glioma, CC [70,71]

Induces the intracellular ROS, decreases Bax Prostate cancer,
Salinomycin [72,73]
translocation to mitochondria Osteoblastoma
Gamitrinibs/TPP Inhibit TRAP1 permeabelizer Anticancer drugs [74-79]
Upregulate CDK inhibitors, G1 arrest, mito-
SMIP004 Prostate cancer [80,81]
chondrial ROS induction
Elesclomol Hsp70 induction, ROS induction Breast cancer [83-85]
Mitochondrial disruption (long MPPs)
MPPs Cancer [86-88]
Cyt c release (short MPPs)
VDAC1-based pep-
Target Bcl-2 family proteins Acute lymphocytic leukemia [89]
tides (Antp)
ATPI Inhibit ATP synthase Psoriasis [90,91]
GI Increase biosynthesis of glutathione MDF [94-96]
RO/NS scavengers

Non-specific antioxi- Nonspecifically quench RO/NS, modulate mito- Metabolic syndrome, diabetes II,
[97-101]
dants, NSA chondrial activity cancer
Stroke, Alzheimer's, Hundgting-
SOD mimetics, SODM Lower SOD levels [102-106]
tons, Parkinsons Diseases
Mt-Targeted Antioxi- Specifically penetrate mitochondria and elimi-
Age-related diseases [106-125]
dants, MTA nate RO/NS; can be rechargable
L-Carnitine Inhibits TGF-B1-induced ROS Neuropathies, myopathies [127-129]
Bioenergetic enhancers (BE)

PQQ Promote mitochondrial biogenesis [130]

Vitamins K1,K2 Rescue Pink1 deficiency Parkinson's disease, cataract [131-132]
Sodium pyruvate, SP Interacts with complex I Encephalopathy, epilepsy [133-134]
Creatine, Cr ATP regeneration, ROS quencher Neurodegeneration [135-137]
Idebenone Inhibits mitochondriogenic responses Friedreich ataxia [138,139]
Parkinsond disease, atrial fibril-
Omega-3 fatty acids Increase SOD2 activity [140-145]
lation
BMD188 - [cis-1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one]; PUFAs - polyunsaturated fatty acids; TrxR - thioredoxin; ESOM (esomeprazole, 5-
Methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2- yl)methylsulfinyl]-3H-benzoimidazole); salinomycin - (2R)-2-[(5S,6R)-6-[(1S,2S,3S,5R)-5-[(2S,5R,7S,9S,
10S,12R,15R)-2-[(2R,5R,6S)-5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl]-15-hydroxy-2,10,12-trimethyl-1,6,8-trioxadispiro[4.1.5^{7}.3^{5}]pentadec-
13-en-9-yl]-2-hydroxy-1,3-dimethyl-4-oxoheptyl]-5-methyl-2-tetrahydropyranyl]butanoic acid; gamitrinib - resorcinolic-based Hsp90 inhibitor; SMIP004 - N-
(4-butyl-2-methylphenyl)acetamide; Elesclomol - N1,N3-dimethyl-N1,N3- bis(phenylcarbonothioyl)propanedihydrazide; GI - glutathione inducers; PQQ -
pyrroloquinoline quinone; Idebenone - 2-(10-hydroxydecyl)-5,6-dimethoxy-3-methyl-cyclohexa-2,5-diene-1,4-dione.
4 Current Medicinal Chemistry, 2015, Vol. 22, No. 1 Lyakhovich and Graifer

potential pharmacological approach for treatment of
many diseases [30]. ROS mediate permeability of mi-
tochondrial transition pore (PTP) and members of Bcl-
2 superfamily including pro- (Bad, Bim, Bax, Bak) and
anti-apoptotic (Bcl-2, Bcl-XL, and Bcl-w) proteins
[31,32]. The mitochondrial outer membrane can be
permeabilized by the release of cytochrome c, activa-
tion of caspases 3/9 and neutralization of mitochondria-
released caspase inhibitors Smac/Diablo and
Omi/HtrA2 [33]. Ii often starts with various death sig-
nals including RO/NS accumulation and concomitant
binding of the pro-apoptotic protein Bax to the outer
mitochondrial membrane followed by the release of the
apoptosis-inducing factor (AIF) to the cytosol [34].
This process is facilitated by intramitochondrial cal-
cium, accumulation of which promotes PTP opening
[35]. The next step leading to apoptosis is activation of
caspases, in particular caspase 9, resulting in DNA
fragmentation and self-digestion of the cell [36]. Anti-
apoptotic protein Bcl-2 preserves binding of Bax with
mitochondria thus leading to the opening of PTP and
initiating apoptosis [37].
Autophagy, also known as cell cannibalism, is a
mechanism that maintains homeostasis in mammalians
[38]. Although based on protein degradation, auto-
phagy leads to cell survival and supplies the cells with
nutrients during starvation or serves as a firewall
against infection and antigen presentation (Fig. 2). Any
alterations in the autophagy are associated with a vari-
ety of disorders, including mycobacterium tuberculosis,
neurodegeneration, age-related renal disorders and can-
cer [39].
3.1. Drugs that Amplify Ros Causing Apoptosis
One of the first drugs disrupting mitochondria with
excess ROS production and triggering apoptosis was
based on alpha-tocopheryl succinate ( -TOS), an ani-
onic analogue of vitamin E. It was reported to increase
ROS levels in some cancer cells and selectively induce
apoptosis [40]. The molecular mechanism of -TOS
action involves interaction with ubiquinone-binding
site of mitochondrial complex II and concomitant inhi-
bition of succinate dehydrogenase (SDH) activity [41].
It is accompanied by recombination with molecular
oxygen to yield ROS and permeabilization of mito-
chondria [42]. In pre-clinical cancer models, -TOS
has revealed a strong potential at inhibiting tumor de-
velopment [43]. Pro-apoptotic drug BMD188 (cis-1-
hydroxy-4-(1-naphthyl)-6-octylpiperidine-2- one) gen-
erates mitochondrial ROS and triggers apoptosis by
activation of caspase-3. It was reported to inhibit the
primary growth of prostate cancer cells [44,45]. Anti-
neoplastic drug LND (Ionidamine, 1-(2,4- dichloroben-
zyl)-1H-indazole-3-carboxylic acid ) is a derivative of
indazole-3-carboxylic acid. It has been shown to inhibit
glycolysis and induce mitochondria-mediated apoptosis
by activation of caspase-9, -3 as well as Akt/mTOR
pathway [46]. Combinatorial treatment of LND with

Fig. (2). Drugs inducing death signaling pathways. ROS or other stimuli (Akt/mTOR) triggers apoptosis through permeabiliza-
tion of PTP mediated by the anti- and proapoptotic factors (Bcl-2, Bax, etc.) followed by release of cytochrome c and activa-
tion of caspases. In turn, mitophagy starts with the formation of a double-layered membrane known as phagophore which en-
gulfs the mitochondrion followed by fusion with a lysosome and consecutive degradation. BCL-2 prevents the induction of
mitophagy by binding Beclin1. Only drugs (bold italic) with more than 10 published references and validated targets (dotted
arrows) are depicted. Akt- protein kinase B (also known as PKB); mTOR -mechanistic Target of Rapamycin; Hsp70 and Hsp
90 - heat shock proteins; Beclin1 - BCL2 interacting protein (aslo known as ATG6); Bcl-2 - B-cell lymphoma 2 protein; BclX1
- B-cell lymphoma-extra large protein; TRAP1 - heat shock mitochondrial protein; PPI - Proton-Pump Inhibitor; LC3 - micro-
tubule-associated protein 1A/1B-light chain 3; PINK1 - PTEN-induced putative kinase 1; Cyt c - cytochrome C.
Drugs Targeting Oxidative Stress in Mitochondria
arsenic trioxide induced apoptosis in leukemia cell
lines [47]. Natural terpenoid aldehyde Gos (gossypol,
2,2-bis-(Formyl-1,6,7-trihydroxy-5-isopropyl-3-methyl-
naphthalene) has been shown to increase ROS and in-
duce apoptosis and necrosis via inhibition of Bcl-2 pro-
teins in multiple myeloma cells [48]. Gos not only in-
duced apoptosis via activation of caspase-3, cyto-
chrome c release from mitochondria and displacing
BH3-only proteins from Bcl-2, but also inhibited IL-6
signaling followed by Bcl-2 dephosphorylation and
Mcl-1 downregulation. [49]. At the same time, Gos
was shown to induce autophagy via ROS activation in
Burkitt lymphoma [50]. Close Gos derivative,
apogossypolone (ApoG2), induces autophagy in sev-
eral cancer cells through Beclin-1-mediated ROS
upregulation in human hepatocellular carcinoma cells
[51].
Polyunsaturated fatty acids (PUFAs) are substrates
for ROS-induced peroxidation reactions [52]. Although
playing an essential role in cell membranes, upon over-
loading they induce ROS production and apoptosis
[53]. The most famous representative, DHA
(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-
hexaenoic acid), was demonstrated to induce both
apoptosis and autophagy by means of mitochondrial
ROS-mediated Akt-mTOR signaling [54]. Carnitine
palmitoyltransferase I catalyzes the conversion of acyl-
CoA to acylcarnitines in mitochondria. This conversion
can be blocked with etomoxir (R(+)-2-[6-(4- Chloro-
phenoxy)hexyl]-oxirane-2-carboxylic acid) which in-
duces ROS production and apoptosis in hepatoma cells
[55]. The etomoxir can also potentiate the activity of
chemotherapeutic anticancer agents, such as cisplatin.
Interestingly, the close drug known as ERGO-1 (Eto-
moxir for the Recovery of Glucose Oxidation) shifts
the metabolic balance of fatty acid oxidation to glucose
oxidation. For that reason, ERGO-1 is used during
heart disease [56]. Other studies with this drug target-
ing OS in leukemia and glioma models support its ap-
plication in anticancer therapy [57, 58].
Thioredoxin inhibitors provide a promising thera-
peutic strategy for cancer prevention and intervention.
A small oxidoreductase thioredoxin (TrxR) alleviates
OS by scavenging ROS thus stimulating cancer cell
survival and inhibiting apoptosis. [59]. Therefore,
blocking its function represents a valuable anticancer
strategy. In particular, Ru(II) polypridyl complexes
with diimine ligands have been suggested and applied
to induce ROS-mediated apoptosis [60]. Auranofin, a
gold(I) compound, was shown to inhibit TrxR and re-
vealed to be effective by inducing apoptosis through
Current Medicinal Chemistry, 2015, Vol. 22, No. 1 5
caspase-3 activation in drug -resistant human chronic
myeloid leukemia cells [61]. Organoselenium com-
pound BBSKE (1,2- [bis(1,2-benzisoselenazolone-
3(2H)-ketone)]ethane) is a TrxR inhibitor which induce
apoptosis via Bcl-2/Bax pathway [62,63]. Since TrxR
mediates resistance to irradiation of a non-small cell
lung cancer, BBSKE has been utilized as a radiosensi-
tizer in some clinical trials.
3.2. Inducers of Mitophagy
MDF is linked to many neurodegenerative and mus-
cular disorders, apoptosis, aging, cancer, and also leads
to mitophagy [64]. The mitophagy serves to remove
dysfunctional mitochondria from the cells and is often
controlled by moderate levels of ROS [65]. During mi-
tophagy dysfunctional mitochondria are engulfed by a
double- layered membrane (phagophore) that forms so-
called autophagosome (Fig. 2). The former one fuses
with a lysosome and forms an autolysosome [66]. Con-
comitantly, a cytosolic form of light chain 3 (LC3) pro-
tein is recruited to autophagosome at membranes. Fi-
nally, the engulfed mitochondria are degraded. Auto-
phagy can be prevented by BCL-2 protein through its
binding to Beclin1, the main mediator of autophagy
[67]. The BH3 domain of Beclin 1 is inhibited by Bcl-
2.
Among several drugs inducing apoptosis proton
pump inhibitor ESOM damages mitochondria through
NADPH oxidase and ROS accumulation [68]. Treat-
ment with the ESOM leads to accumulation of auto-
phagosomes and reduces the autophagic flux. In addi-
tion, ESOM decreases mTOR signaling. The ESOM
may work as a synthetic lethal reagent which increase
cytotoxicity if used upon knockdown of Beclin-1 [69].
Another drug DCA (dichloroacetate) is a small mole-
cule and a mitochondria-targeting agent. DCA admini-
stration was demonstrated to decrease mitochondrial
membrane potential by inducing the ROS production
and inhibiting the expression of Hsp70 in tumor tissues
[70]. In cancer cells, the DCA induces mitophagy
through accumulation of ROS, reduction of lactate
excretion followed by the increase of NAD(+)/NADH
ratio [71]. A negative regulator against cell apoptosis
and mitophagy, salinomycin, induces the intracellular
ROS level, decreases membrane potential of mitochon-
dria thus activating the caspase-3 mediated cytochrome
c release to the cytoplasm [72]. Inhibition of late stages
of autophagy by the salinomycin was shown to increase
ROS production and impair MDF quality control. This
chemical increases cytosolic sodium concentrations
and causes cytosolic calcium release [73]. Shepherdin,
6 Current Medicinal Chemistry, 2015, Vol. 22, No. 1
one of the first rationally designed mitochondrial drugs
targeting Hsp90/TRAP1 functions through inhibiting
ATPase activities. The tumor necrosis factor (TNF)
receptor-associated protein 1 (TRAP1), alternatively
known as heat shock protein 75 (Hsp75), is a mito-
chondrial homologue of Hsp90 [74]. Loss of the chap-
erone functions was reported to specifically kill cancer
cells by induction of mitochondrial membrane perme-
abilization [75]. Phosphorylation of TRAP1 by PTEN
induced putative kinase 1 (PINK1) is responsible for
the protection of ROS-mediated cell death [76]. There-
fore, the initial design was to block the ATP pocket in
the Hsp90 N domain which would cause inhibition of
the TRAP1 chaperone function because much literature
has demonstrated that TRAP1 plays an important role
in inhibiting ROS-mediated cell death [77]. However,
the location of TRAP1 in mitochondria created a deliv-
ery problem which was solved by designing a penetrat-
ing peptide with amino acid sequence
RQIKIWFQNRRMKWKK. Shepherdin contains an
amino acid sequence from survivin, KHSSGCAFL,
which is involved in the interaction with Hsp90,
whereas a prototype Hsp90 inhibitor, geldanamycin,
inhibits Hsp90 and TRAP1. Gamitrinib-G4 and TPP
covalently link mitochondrial targeting module, tetra-
cyclicguaidinium or triphenylphosphonium, and
Hsp90/TRAP1 inhibition module, geldanamycin [78].
The above solutions developed a feasible strategy to
design a novel class of anticancer drugs [75]. Further-
more, considering the mitochondria-targeted delivery
and direct induction of MMP, gamitrinib could sensi-
tize the mitochondria to a variety of cell death stimuli
using an entirely different mechanism from other can-
cer drugs [79]. SMIP004 (N-(4-butyl-2-methyl-phenyl)
acetamide) is a novel anticancer drug which has been
applied to treat human prostate cancer [80]. The drug
induces mitochondrial ROS formation and disrupts the
balance between redox and bioenergetics states [81].
The same principle has been applied when designing a
series of pro-oxidant malonohydrazides that have been
used as anticancer agents targeting the redox state of
pathogenic versus non-pathogenic cells. The most de-
veloped drug of this class, STA-4783 (elesclomol) tar-
gets OS by Hsp70 induction and induces ROS within
cancer cells [83-85].
3.3. Mitochondria Permeabilizers
A significant breakthrough has been achieved in the
development of lipophilic and cationic peptides that
facilitate permeation of the hydrophobic mitochondrial
membrane. Such mitochondria-penetrating peptides
(MPP) may act as mitochondrial disrupters and at the
Lyakhovich and Graifer
same time serve as vehicles for the delivery of bioac-
tive agents to enhance death signaling pathways
[86,87]. Importantly, the length of such peptides de-
fined the mode of their action. Longer peptides in-
creased membrane permeability, whereas the shorter
ones could activate the permeability transition pore
complex (PTPC) and led to the cytochrome c release
[88]. MPPs can bypass drug resistance by allowing mi-
tochondria to accommodate chemotherapeutic drugs
that otherwise would meet MDR barrier. In order to
facilitate mitochondrial drug delivery, delocalized lipo-
philic cations were included in the peptide sequence
[87]. VDAC1, a mitochondrial voltage-dependent an-
ion channel 1, may serve as a pro-apoptotic target to
design MPP-related drugs. Among many MMP drugs
synthesized so far, Antp-LP4 and N-Terminal-Antp
revealed pharmacological activities against chronic
lymphocytic leukemia [89]. ATP synthase inhibitors
(ATPI) include 1,4-benzodiazepine (-imino ATP, Bz-
423), AMP-PNP and Mg(2+)/ADP have been demon-
strated to have potential in controlling disorders of im-
mune function [90]. Another mitochondrial drug Bz-
423 is a modulator of the F(1)F(0)- ATPase. It induces
the formation of superoxide anion that acts as a second
messenger to activate Bax and Bak and initiate apopto-
sis [91].
4. DRUGS ELIMINATING RO/NS
The recent recognition of mitochondria as an organ-
elle responsible for a variety of functions ranging from
cell death to inflammation and cancer development has
drawn awareness for developing chemicals to protect
mitochondria against RO/NS [92,93]. Historically,
those compounds that inhibit the oxidation of other
molecules and protect cells against ROS (and very of-
ten against RNS) are called antioxidants. Here, we will
focus only on chemical antioxidants that interact either
non-specifically or specifically with mitochondrial
network of antioxidant enzymes (Fig. 3). Although
non-specific antioxidants can eliminate RO/NS from
the whole cells but for simplicity, we will focus only
on the drugs targeting mitochondrial or mitochondria-
mediated RO/NS, including compounds involving de-
toxification pathways but excluding antioxidant me-
tabolites (Table 1).
4.1. Antioxidants and Non-Specific RO/NS Scaven-
gers
One of the earliest class of drugs that reduce RO/NS
was that chemicals increasing biosynthesis of detoxify-
ing enzymes. One group of such compounds is glu-
tathione inducers (GI), which include N-acetylcysteine
Drugs Targeting Oxidative Stress in Mitochondria
Fig. (3). Drugs removing RO/NS or enhancing mitochon-
drial functions. Two groups of chemicals can be used to
eliminate RO/NS or facilitate bioenergetic functions of mito-
chondria. The first one includes antioxidants that scavenge
RO/NS either specifically or non-specifically targeting mito-
chondria. The second group includes so- called mitochon-
drial nutrients aiming to enhance bioenergetics functions of
these drugs (bold italic) with more than 10 published refer-
ences and validated targets (dotted arrows) are depicted.
TGF-B1 - Transforming growth factor beta 1 or TGF-1;
ETC - electron transport chain; TSA- Krebs cycle; SOD -
superoxide dismutase;
(NAC) [94], pantothenic acid [95] and curcumin [96].
Since administration of these GI increased glutathione
content by non- defined mechanism in the whole cell,
and not only in mitochondrion, pharmacological appli-
cation of these compounds has not been approved by
FDA as pure mitochondrial drugs. Other compounds of
the same group are naturally present in the cell and act
as intracellular nonspecific antioxidants (NA). They
include ascorbic acid [97,98], -carotene [99], -lipoic
acid [100] and resveratrol [101]. The second group of
antioxidants is SOD mimetics (SODM) [102]. It in-
cludes sodium thiopental [103,104] and propofol (2,5-
dihydro-5-oxo-1- phenil -1H-1,2,4- triazole-3-
carboxylic acid dimethylamide) [105] which are used
to treat various forms of brain traumas including reper-
fusion injuries [106].
The breakthrough in the area of natural antioxidants
occurred since the introduction of ubiquinol (2,3-
dimethoxy-5-methyl-6-poly prenyl-1,4-benzoquinol),
the reduced (electron-rich) form of coenzyme Q10
which plays an important role in mediating mitochon-
drial complexes I-III and thus can be specifically deliv-
ered to mitochondria [107, 108]. Although much hope
has been expressed to ubiquinone as potential anti-
aging remedies in reducing consequences of Alz-
heimer's [109], Huntington's [110], Parkinson's
Current Medicinal Chemistry, 2015, Vol. 22, No. 1 7
[111,112] and other neurological diseases [113], the
prooxidative properties of this chemical under certain
conditions represent a significant drawback for this
[114]. In general, one should be aware that many of the
described compounds possess dual properties and can
enhance cellular bioenergetics pathways or scavenge
RO/NS or play a role of either pro- or antioxidant de-
pending on cellular status (also depicted in Fig. 1). This
may create a potential problem hence finding a wider
pharmacological window represents a challenging
task for future research.
The best characterized lipophilic agent to deliver
antioxidative drugs to mitochondria is the TPP
(triphenylphosphonium) cation [115]. Among numer-
ous conjugates of antioxidants and the TPP, the most
prominent ones are ebselen (2-Phenyl-1,2- benzisose-
lenazol-3(2H)-one) [116], lipoic acid [117], nitroxides
[118, 119], ubiquinonyl-decyl-triphenylphosphonium
(MitoQ) [120] and plastoquinone (1,4-benzoquinone
quinone Coenzyme Q10) [121]. The former one, repre-
sented by 10-(6'- Plastoquinonyl)decyltriphenyl-
phosphonium (SkQ) derivatives, are rechargeable anti-
oxidants that revealed blocked ROS-induced apoptosis
and necrosis in subnanomolar amounts. In mammals,
SkQs demonstrated effectiveness by inhibition of de-
velopment cataract, osteoporosis, thymus involution
and numerous other abnormalities [122,123]. Although
both MitoQ (developed by Dr.Murphy's team) and SkQ
(developed by Dr. Skulachev's team) have many things
in common (both utilizes 3-phenyl-phosphonium "tug-
boat"), the former one has plastoquinone, instead of
ubiquinone and has advantage over MitoQ as having a
wider range of effective dosage. The second approach
for delivering antioxidative agents to mitochondria is
through the use of Szeto-Schiller (SS)-peptides [124].
SS- peptides comprise positively charged compounds
having four basic amino acids [125].
4.2. Bioenergetic Enhancers (BE)
Mitochondrial biogenesis, defined as the gain of mi-
tochondrial mass of the cell, is maintained by fusion
and fission processes and is largely coordinated by oxi-
dative stimulus, cell energy requirements and other fac-
tors [126]. One way to enhance the mitochondrial bio-
genesis by pharmacological agents is to activate some
specific pathways through PGC-1, sirtuins, AMPK or
other key molecules. Another approach is to supply the
cells directly with so-called bioenergetics enhancers -
supplements that facilitate RO/NS detoxification and
concomitantly improve mitochondrial functions. Those
supplements, often called mitochondrial nutrients, are
8 Current Medicinal Chemistry, 2015, Vol. 22, No. 1
especially helpful during MDF occurred due to muta-
tions in some genes (DJ-1, parkin, PINK1 or LRRK2)
which may cause defects in mitochondrial dynamics.
Some of those nutrients (vitamin c, MitoQ, lipoic acid)
sharing similar functions are already presented in the
above mentioned group of antioxidants.
L-Carnitine (4-N-trimethylammonium-3-
hydroxybutric acid) participates in transport of fatty
acid from cytoplasm to mitochondria for energy pro-
duction and may also quench free radicals [127]. L-
carnitine can effectively protect ischemia-reperfusion
injury in the kidney [128]. On a molecular level, the L-
carnitine is thought to inhibit TGF-1-induced mtROS
[129]. Quinoproteins - are enzymes containing pyr-
roloquinoline quinone (PQQ) for which antioxidant and
neuro-protective effects were found to protect mito-
chondria from OS and promote mitochondrial biogene-
sis. [130]. Vitamin K2 is a mitochondrial electron car-
rier that rescues PINK1 deficiency1 [131] and vitamin
K1 may protect cataract formation in the diabetic rat
models [132]. Another extracellular antioxidant, so-
dium pyruvate (SP), is a substrate of the tricarboxylic
acid cycle. SP has been proposed for the treatment of
hypoxic-ischemic encephalopathy [133]. In combina-
tion with other BE, SP was shown to restore bioener-
getic homeostasis in the brain and suggested as anti-
seizure agent during epilepsy [134]. Creatine (Cr), a
nitrogenous organic acid, exerts beneficial effects on a
variety of MDF pathologies [135]. It improves myo-
cardial function, mitochondrial respiration during
reperfusion injury [136] and prevents ROS formation
in neurodegenerative diseases [137]. Coenzyme Q ana-
logue idebenone serves as a mitochondrial protector
against OS. It inhibits mitochondriogenic responses in
Friedreich ataxia [138,139]. Omega-3 polyunsaturated
fatty acids enhance bioenergetics function of mito-
chondria by increasing SOD2 activity [140]. Not sur-
prisingly, these chemicals have been used against the
outcome of symptoms associated with schizophrenia
[141], Parkinson's disease [142,143], age-related disor-
ders [144] and were recommenden as cardioprotectors
[145].
5. CONCLUSION: DOUBLE-EDGED SWORD OF
ANTIOXIDANTS AND PRINCIPLES FOR
DESIGNING IDEAL MITOCHONDRIAL DRUGS
The purpose of this mini -review was to present a
recent progress made for the last decade in developing
therapeutically applied substances targeting mitochon-
dria- mediated OS. These substances have a variety of
pharmacological modalities including anticancer prop-
Lyakhovich and Graifer
erties, immunosuppression, or potassium channel trig-
gering. Most of them deal with either removal of
RO/NS or amplifying RO/NS-mediated death path-
ways. The critical question, however, is whether ex-
cess of RO/NS is really detrimental. Although OS con-
tributes to mitochondrial damage in a range of pa-
thologies, there is still a considerable doubt as to
whether RO/NS pharmacological elimination is bene-
ficial or harmful. RO/NS can benefit to the immune
system against pathogens [146] and perform an essen-
tial role in redox signaling [147]. A number of kinase
signaling pathways are affected by RO/NS [148]. Even
in early stages of pathological conditions they may be
helpful as part of a self-clearing machinery including
autophagy and apoptosis [30,36,40]. Therefore, anti-
oxidant systems not only remove oxidants but also
maintain them at an optimum level [149]. Therefore,
targeting RO/NS upon designing novel therapeutic
strategy is associated with some difficulties and should
be considered with extra care. On the contrary, elimi-
nation of RO/NS by antioxidants is warranted and
necessary in pathological conditions. In this regard,
BE are good examples of chemopreventive agents di-
rected against aging, diabetes, or cancer. Besides ob-
vious pharmacological properties (low toxicity, sub-
nanomolar active concentrations, solubility, oral
bioavailability), the following principles should be
taken into account when rationally designing mito-
chondria-mediated RO/NS targeting drugs. For the
above mentioned group I that comprises the agents
inducing cell death pathways, the principles of drug
design should be as following: (i) they should tran-
siently interact with proteins that block apoptosis or
autophagy to allow sufficient RO/NS accumulation;
(ii) ideally, those drugs should have a neutralizer, an
antagonistic pair with higher affinity to the drug and
lower affinity to surrounding molecules; (iii) they
should have a specific moiety for selective delivery to
mitochondria; (iv) upon interaction, the resulting
products should not produce any adverse side-effects.
In turn, for the group II of mitochondria-targeted anti-
oxidants and bioenergetics enhancers: (i) they should
be stable small molecules that can be specifically up-
taken by mitochondria; (ii) they should block oxidative
damage with higher efficiency and be physiologically
tolerant, preferably from natural compounds; (iii) they
should be recyclable and convert back to the active
antioxidant form; (iv) as in the group I, they should
have a neutralizing pair molecule to be administrated
once the clinical benefit is reached. Such neutralizers
have been recently developed for gastro-enterological
disorder. For example, Ac-PPP-tet from Shiga toxin
Drugs Targeting Oxidative Stress in Mitochondria Current Medicinal Chemistry, 2015, Vol. 22, No. 1 9

that functions in the intestine by altering the intracellu- GRAPHICAL ABSTRACT

lar transport of Stx2 in epithelial cells and blocks the
Drugs targeting mitochondria-mediated ROS can be
intracellular transport of Stx2 from the Golgi apparatus
either cytotoxic compounds aiming to promote cell
to the endoplasmic reticulum may be utilized to cleave
death pathways or chemicals aiming to eliminate ROS
mitochondrial peptide-disruptors [150].
and enhance mitochondrial functions.
Although only a few drugs for mitochondrial dis-
ease have reached early phases of the FDA drug devel- CONFLICT OF INTEREST
opment approval process, chemicals eliminating The authors confirm that this article content has no
RO/NS or promoting death pathways have been al- conflict of interest.
ready implied. In light with the above strategy, we
highlighted in bold the drugs which most likely possess ACKNOWLEDGEMENTS
therapeutic values (Table 1).
We would like to thank all anonymous reviewers for
LIST OF ABBREVIATIONS valuable comments. We are also thankful to Dr. Rakesh
Aithal (Masaryk University) for careful reading this
DDR = Damage and repair paper. AL is sponsored by the Institutional grant of In-
RO/NS = Reactive oxygen/nitrogen species ternational Clinical Research Center (ICRC) of St.
Anne's University Hospital, Brno, Czech Republic
MDF = Mitochondrial dysfunction
OxPhos = Oxidative phosphorylation REFERENCES
MRD = Mitochondria-related disorders [1] Benz, C.C.; Yau, C. Ageing, oxidative stress and cancer:
paradigms in parallax. Nat. Rev. Cancer, 2008, 8(11), 875-
P = Mitochondrial membrane proton gradient 879.
[2] Pagano, G.; Shyamsunder, P.; Verma, R.; Lyakhovich, A.
OS = Oxidative stress Damaged mitochondria in Fanconi anemia - an isolated
event or a general phenomenon? Oncoscience, 2014, 4,
CoQ = Coenzymes Q 187-296.
RET = Reverse electron transport [3] Chen, E.I. Mitochondrial dysfunction and cancer metastasis.
J. Bioenerg. Biomembr., 2012, 44(6), 619-622.
NOS = Nitric synthase [4] Wallace, D.C. Bioenergetic origins of complexity and dis-
ease. Cold Spring Harb Symp Quant Biol., 2011, 76, 1-16.
mtNOS = Mitochondrial NO synthase [5] Heller, A.; Brockhoff, G.; Goepferich, A. Targeting drugs
to mitochondria. Eur J Pharm Biopharm., 2012, 82(1), 1-
SOD = Superoxide dismutase 18.
[6] Votyakova, T. V.; Reynolds, I. J. m-Dependent and -
GPx = Glutathione reductase independent production of reactive oxygen species by rat
GST = Glutathione S-transferase brain mitochondria. J. Neurochem.., 2001, 79, 266-277.
[7] Adam-Vizi, V.; Chinopoulos C. Bioenergetics and the for-
MTP = Mitochondrial transition pore mation of mitochondrial reactive oxygen species. Trends
Pharmacol. Sci., 2006, 27, 639-645.
BCL = B-cell lymphoma 2 [8] Sugioka, K.; Nakano, M.; Naito, I.; Tero-Kubota, S.; Ike-
gami, Y. Properties of a coenzyme, pyrroloquinoline qui-
AIF = Apoptosis-inducing factor none: generation of an active oxygen species during a re-
duction-oxidation cycle in the presence of NAD(P)H and
-TOS = Alpha-tocopheryl succinate O2. Biochim Biophys Acta, 1988, 964(2), 175-182.
PUFAs = Polyunsaturated fatty acids [9] Sawa, T.; Ihara, H.; Ida, T.; Fujii, S.; Nishida, M.; Akaike,
T. Formation, signaling functions, and metabolisms of ni-
SDH = Succinate dehydrogenase trated cyclic nucleotide. Nitric Oxide, 2013, 34, 10-18.
[10] Saeidnia, S.; Abdollahi, M. Toxicological and pharmacol-
PTPC = Permeability transition pore complex ogical concerns on oxidative stress and related diseases.
Toxicol Appl Pharmacol., 2013, 273(3), 442-455.
MDR = Multi-drug resistance [11] Wang, X.; Peralta, S.; Moraes, C.T. Mitochondrial altera-
tions during carcinogenesis: a review of metabolic trans-
VDAC = Voltage-dependent anion channel formation and targets for anticancer treatments. Adv Cancer
PTEN = Phosphatase and tensin homolog Res., 2013, 119, 127-160.
[12] Kussmaul, L.; Hirst, J. The mechanism of superoxide pro-
BH3 = Bcl-2 homology domain 3 duction by NADH:ubiquinone oxidoreductase (complex I)
from bovine heart mitochondria. Proc. Natl. Acad. Sci.
TrxR = Thioredoxin USA, 2006, 103, 7607-7612.
[13] Kushnareva, Y.; Murphy, A.N.; Andreyev, A. Complex I-
NAC = N-acetylcysteine mediated reactive oxygen species generation: modulation
10 Current Medicinal Chemistry, 2015, Vol. 22, No. 1
by cytochrome c and NAD(P)+oxidation-reduction state.
Biochem. J., 2002, 368, 545-553.
[14] Guzy, R.D.; Schumacker, P.T. Oxygen sensing by mito-
chondria at complex III: the paradox of increased reactive
oxygen species during hypoxia. Exp. Physiol., 2006, 91,
807-819.
[15] Mailloux, R.J.; Jin, X.; Willmore, W.G. Redox regulation
of mitochondrial function with emphasis on cysteine oxida-
tion reactions. Redox Biol., 2013, 2, 123-139.
[16] Vamecq, J.; Dessein, A.F.; Fontaine, M.; Briand, G.;
Porchet, N.; Latruffe, N.; Andreolotti, P.; Cherkaoui-Malki,
M. Mitochondrial dysfunction and lipid homeostasis. Curr
Drug Metab., 2012, 13(10), 1388-1400.
[17] Ferreira, I.L.; Resende, R.; Ferreiro, E.; Rego, A.C.;
Pereira, C.F. Curr Drug Targets, 2010, 11(10), 1193-1120.
[18] Chaturvedi, R.K.; Flint, B. M. Mitochondrial diseases of the
brain. Free Radic Biol Med., 2013, 63, 1-29.
[19] Phillips, D.C.; Dias, H.K.; Kitas, G.D.; Griffiths, H.R. Ab-
errant reactive oxygen and nitrogen species generation in
rheumatoid arthritis (RA): causes and consequences for
immune function, cell survival, and therapeutic interven-
tion. Antioxid Redox Signal, 2010, 12(6), 743-785.
[20] Mittal, M.; Siddiqui, M.R.; Tran, K.; Reddy, S.P.; Malik,
A.B. Reactive oxygen species in inflammation and tissue
injury. Antioxid Redox Signal, 2014, 20(7), 1126-1167.
[21] Rochette, L.; Lorin, J.; Zeller, M.; Guilland, J.C.; Lorgis,
L.; Cottin, Y.; Vergely, C. Nitric oxide synthase inhibition
and oxidative stress in cardiovascular diseases: possible
therapeutic targets? Pharmacol Ther., 2013, 140(3), 239-
257.
[22] Murphy, M.P. How mitochondria produce reactive oxygen
species. Biochem J., 2009, 417(1), 1-13.
[23] Tokarz, P.; Kaarniranta, K.; Blasiak, J. Biogerontology,
2013, 14(5), 461-482.
[24] Lu, J.; Holmgren, A. The thioredoxin antioxidant system.
Free Radic Biol Med., 2014, 66, 75-87.
[25] Yuzhalin, A.E.; Kutikhin, A.G. Inherited variations in the
SOD and GPX gene families and cancer risk. Free Radic
Res., 2012, 46(5), 581-599.
[26] Reszka, E.; Wasowicz, W.; Gromadzinska, J. Genetic
polymorphism of xenobiotic metabolising enzymes, diet
and cancer susceptibility. J. Br J Nutr., 2006, 96(4), 609-
619.
[27] Pagano, G.; Talamanca, A.A.; Castello, G.; d'Ischia, M.;
Pallard, F.V.; Petrovi, S.; Porto, B.; Tiano, L.; Zatterale,
A. From clinical description, to in vitro and animal studies,
and backward to patients: oxidative stress and mitochon-
drial dysfunction in Fanconi anemia. Free Radic Biol Med.,
2013, 58, 118-125.
[28] Wang, C.H.; Wu, S.B.; Wu, Y.T.; Wei, Y.H. Oxidative
stress response elicited by mitochondrial dysfunction: im-
plication in the pathophysiology of aging. Exp Biol Med.,
2013, 238(5), 450-460.
[29] Pagano, G.; Castello, G.; Pallard, F.V. Sjgren's syn-
drome-associated oxidative stress and mitochondrial dys-
function: prospects for chemoprevention trials. Free Radic
Res., 2013, 47(2), 71-73.
[30] Ralph, S.J.; Neuzil, J. Mitochondria as targets for cancer
therapy. Mol Nutr Food Res., 2009, 53(1), 9-28.
[31] Skulachev, V.P. Mitochondria in the programmed death
phenomena; a principle of biology: "it is better to die than
to be wrong". IUBMB Life, 2000, 49(5), 365-73.
[32] Wang, K. Molecular mechanisms of hepatic apoptosis. Cell
Death Dis., 2014; 5:e996.
[33] Circu, M.L.; Aw, T.Y. Reactive oxygen species, cellular
redox systems, and apoptosis. Free Radic Biol Med., 2010,
48(6), 749-762.
Lyakhovich and Graifer
[34] Marzetti, E.; Calvani, R.; Cesari, M.; Buford, T.W.;
Lorenzi, M.; Behnke, B.J.; Leeuwenburgh, C. Mitochon-
drial dysfunction and sarcopenia of aging: from signaling
pathways to clinical trials. Int J Biochem Cell Biol., 2013,
45(10), 2288-2301.
[35] Murphy, M.P. Modulating mitochondrial intracellular loca-
tion as a redox signal. Sci Signal, 2012, 5(242), pe39.
[36] Yuan, S.; Akey, C.W. Apoptosome structure, assembly, and
procaspase activation. Structure, 2013, 21(4), 501-515.
[37] Krishna, S.; Low, I.C.; Pervaiz, S. Regulation of mitochon-
drial metabolism: yet another facet in the biology of the on-
coprotein Bcl-2. Biochem J., 2011, 435(3), 545-551.
[38] Filomeni, G.; De, Z, D.; Cecconi, F. Oxidative stress and
autophagy: the clash between damage and metabolic needs.
Cell Death Differ., 2014, doi: 10.1038/cdd.2014.150.
[39] Aki, T.; Funakoshi, T.; Unuma, K.; Uemura, K. Impairment
of autophagy: from hereditary disorder to drug intoxication.
Toxicology, 2013, 311(3), 205-215.
[40] Zhao, Y.; Li, R.; Xia, W.; Neuzil, J.; Lu, Y.; Zhang, H.;
Zhao, X.; Zhang, X.; Sun, C.; Wu, K. Bid integrates intrin-
sic and extrinsic signaling in apoptosis induced by alpha-
tocopheryl succinate in human gastric carcinoma cells.
Cancer Lett., 2010, 288(1), 42-49.
[41] Dong, L.F.; Low, P.; Dyason, J.C.; Wang, X.F.; Prochazka,
L.; Witting, P.K.; Freeman, R.; Swettenham, E.; Valis, K.;
Liu, J.; Zobalova, R.; Turanek, J.; Spitz, D.R.; Domann,
F.E.; Scheffler, I.E.; Ralph, S.J.; Neuzil, J. Alpha-
tocopheryl succinate induces apoptosis by targeting ubiqui-
none-binding sites in mitochondrial respiratory complex II.
Oncogene, 2008, 27(31), 4324-4335.
[42] Gogvadze, V.; Norberg, E.; Orrenius, S.; Zhivotovsky, B.
Involvement of Ca2+ and ROS in alpha-tocopheryl succi-
nate-induced mitochondrial permeabilization. Int J Cancer,
2010, 127(8), 1823-1832.
[43] Angulo-Molina, A.; Reyes-Leyva, J.; Lpez-Malo, A.;
Hernndez, J. The role of alpha tocopheryl succinate (-
TOS) as a potential anticancer agent. Nutr Cancer, 2014,
66(2), 167-176.
[44] Tang, D.G.; Li, L.; Zhu, Z.; Joshi, B.; Johnson, C.R.; Mar-
nett, L.J.; Honn, K.V.; Crissman, J.D.; Krajewski, S.; Reed,
J.C.; Timar, J.; Porter, A.T. BMD188, A novel hydroxamic
acid compound, demonstrates potent anti-prostate cancer ef-
fects in vitro and in vivo by inducing apoptosis: require-
ments for mitochondria, reactive oxygen species, and prote-
ases. Pathol Oncol Res., 1998, 4(3), 179-190.
[45] Chandra, D.; Choy, G.; Tang, D.G. Cytosolic accumulation
of HSP60 during apoptosis with or without apparent mito-
chondrial release: evidence that its pro-apoptotic or pro-
survival functions involve differential interactions with
caspase-3. J Biol Chem., 2007, 282(43), 31289-31301.
[46] Hulleman, E.; Kazemier, K.M.; Holleman, A.; Vander-
Weele, D.J.; Rudin, C.M.; Broekhuis, M.J.; Evans, W.E.;
Pieters, R.; Den Boer, M.L. Inhibition of glycolysis modu-
lates prednisolone resistance in acute lymphoblastic leuke-
mia cells. Blood, 2009, 113(9), 2014-2021.
[47] Calvio, E.; Esta, M.C.; Simn, G.P.; Sancho, P.; Boyano-
Adnez, M. C.; de Blas, E.; Brard, J.; Aller, P. Increased
apoptotic efficacy of lonidamine plus arsenic trioxide com-
bination in human leukemia cells. Reactive oxygen species
generation and defensive protein kinase (MEK/ERK,
Akt/mTOR) modulation. Biochem Pharmacol., 2011,
82(11), 1619-1629.
[48] Xu, R.; Tian, E.; Tang, H.; Liu, C.; Wang, Q. Proteomic
analysis of gossypol induces necrosis in multiple myeloma
cells. Biomed Res Int., 2014, 2014, 839232.
[49] Sadahira, K.; Sagawa, M.; Nakazato, T.; Uchida, H.; Ikeda,
Y.; Okamoto, S.; Nakajima, H.; Kizaki, M. Gossypol in-
duces apoptosis in multiple myeloma cells by inhibition of
Drugs Targeting Oxidative Stress in Mitochondria
interleukin-6 signaling and Bcl-2/Mcl-1 pathway. Int J On-
col., 2014 doi: 10.3892/ijo.2014.2652.
[50] Ni, Z.; Dai, X.; Wang, B.; Ding, W.; Cheng, P.; Xu, L.;
Lian, J.; He, F. Natural Bcl-2 inhibitor (-)- gossypol induces
protective autophagy via reactive oxygen species-high mo-
bility group box 1 pathway in Burkitt lymphoma. Leuk
Lymphoma., 2013, 54(10), 2263-2268.
[51] Cheng, P.; Ni, Z.; Dai, X.; Wang, B.; Ding, W.; Rae S. A.;
Xu, L.; Wu, D.; He, F.; Lian, J. The novel BH-3 mimetic
apogossypolone induces Beclin-1- and ROS-mediated auto-
phagy in human hepatocellular carcinoma [corrected]
cells. Cell Death Dis., 2013, 4, e489.
[52] Al-Gubory, K.H. Mitochondria: omega-3 in the route of
mitochondrial reactive oxygen species. Int J Biochem Cell
Biol., 2012, 44(9), 1569-1573.
[53] Legrand-Poels, S.; Esser, N.; L'homme, L.; Scheen, A.;
Paquot, N.; Piette, J. Free fatty acids as modulators of the
NLRP3 inflammasome in obesity/type 2 diabetes. Biochem
Pharmacol., 2014, doi: 0.1016/j.bcp.2014.08.013.
[54] Shin, S.; Jing, K.; Jeong, S.; Kim, N.; Song, K.S.; Heo,
J.Y.; Park, J.H.; Seo, K.S.; Han, J.; Park, J.I.; Kweon, G.R.;
Park, S.K.; Wu, T.; Hwang, B.D.; Lim, K. The omega-3
polyunsaturated fatty acid DHA induces simultaneous
apoptosis and autophagy via mitochondrial ROS-mediated
Akt-mTOR signaling in prostate cancer cells expressing
mutant p53. Biomed Res Int., 2013, 2013, 568671.
[55] Hernlund, E.; Ihrlund, L.S.; Khan, O.; Ates, Y.O.; Linder,
S.; Panaretakis, T.; Shoshan, M.C. Potentiation of che-
motherapeutic drugs by energy metabolism inhibitors 2-
deoxyglucose and etomoxir. Int J Cancer, 2008, 123(2),
476-483.
[56] Holubarsch, C.J.; Rohrbach, M.; Karrasch, M.; Boehm, E.;
Polonski, L.; Ponikowski, P.; Rhein, S. A double-blind ran-
domized multicentre clinical trial to evaluate the efficacy
and safety of two doses of etomoxir in comparison with
placebo in patients with moderate congestive heart failure:
the ERGO (etomoxir for the recovery of glucose oxidation)
study. Clin Sci (Lond)., 2007, 113(4), 205-212.
[57] Iversen, P.O.; Srensen, D.R.; Tronstad, K.J.; Gudbrandsen,
O.A.; Rustan, A.C.; Berge, R.K.; Drevon, C.A. A bioac-
tively modified fatty acid improves survival and impairs
metastasis in preclinical models of acute leukemia. Clin
Cancer Res., 2006, 12, 3525-3231.
[58] Berge, K.; Tronstad, K.J.; Bohov, P.; Madsen, L.; Berge,
R.K. Impact of mitochondrial beta-oxidation in fatty acid-
mediated inhibition of glioma cell proliferation. J Lipid
Res., 2003, 44(1), 118-127.
[59] An, N.; Kang, Y. Thioredoxin and hematologic malignan-
cies. Adv Cancer Res., 2014, 122, 245-279.
[60] Luo, Z.; Yu, L.; Yang, F.; Zhao, Z.; Yu, B.; Lai, H.; Wong,
K.H.; Ngai, S.M.; Zheng, W.; Chen, T. Ruthenium
polypyridyl complexes as inducer of ROS-mediated apop-
tosis in cancer cells by targeting thioredoxin reductase.
Metallomics, 2014, 6(8), 1480-1490.
[61] Liu, J.J.; Liu, Q.; Wei, H.L.; Yi, J.; Zhao, H.S.; Gao, L.P.
Inhibition of thioredoxin reductase by auranofin induces
apoptosis in adriamycin-resistant human K562 chronic
myeloid leukemia cells. Pharmazie, 2011, 66(6), 440-444.
[62] Wang, L.; Fu, J.N.; Wang, J.Y.; Jin, C.J.; Ren, X.Y.; Tan,
Q., Li, J.; Yin, H.W.; Xiong, K.; Wang, T.Y.; Liu, X.M.;
Zeng, H.H. Selenium-containing thioredoxin reductase in-
hibitor ethaselen sensitizes non-small cell lung cancer to ra-
diotherapy. Anticancer Drugs, 2011, 22(8), 732-740.
[63] Xing, F.; Li, S.; Ge, X.; Wang, C.; Zeng, H.; Li, D.; Dong,
L. The inhibitory effect of a novel organoselenium com-
pound BBSKE on the tongue cancer Tca8113 in vitro and
in vivo. Oral Oncol., 2008, 44(10), 963-969.
Current Medicinal Chemistry, 2015, Vol. 22, No. 1 11
[64] Tao, M.; You, C.P.; Zhao, R.R.; Liu, S.J.; Zhang, Z.H.;
Zhang, C.; Liu, Y. Animal mitochondria: evolution, func-
tion, and disease. Curr Mol Med., 2014, 14(1), 115-124.
[65] Dorn, G.W.; Kitsis, R.N. The Mitochondrial Dynamism-
Mitophagy-Cell Death Interactome: Multiple Roles Per-
formed by Members of a Mitochondrial Molecular Ensem-
ble. Circ Res., 2014, pii:CIRCRESAHA.114.303554.
[66] Frank, M.; Duvezin-Caubet, S.; Koob, S.; Occhipinti, A.;
Jagasia, R.; Petcherski, A.; Ruonala, M.O.; Priault, M.; Sa-
lin, B.; Reichert, A.S. Mitophagy is triggered by mild oxi-
dative stress in a mitochondrial fission dependent manner.
Biochim Biophys Acta., 2012, 1823(12), 2297-2310.
[67] Tanida, I. Autophagosome formation and molecular mecha-
nism of autophagy. Antioxid Redox Signal, 2011, 14(11),
2201-2214.
[68] Houten, S.M.; Denis, S.; Te Brinke, H.; Jongejan, A.; van
Kampen, A.H.; Bradley, E.J.; Baas, F.; Hennekam, R.C.;
Millington, D.S.; Young, S.P.; Frazier, D.M.; Gucsavas-
Calikoglu, M.; Wanders, R.J. Mitochondrial NADP(H) de-
ficiency due to a mutation in NADK2 causes dienoyl-CoA
reductase deficiency with hyperlysinemia. Hum Mol Genet.,
2014, 23(18), 5009-5016.
[69] Marino, M.L.; Fais, S.; Djavaheri-Mergny, M.; Villa, A.;
Meschini, S.; Lozupone, F.; Venturi, G.; Della Mina, P.;
Pattingre, S.; Rivoltini, L.; Codogno, P.; De Milito, A. Pro-
ton pump inhibition induces autophagy as a survival
mechanism following oxidative stress in human melanoma
cells. Cell Death Dis., 2010, 1, e87.
[70] Duan, Y.; Zhao, X.; Ren, W.; Wang, X.; Yu, K.F.; Li, D.;
Zhang, X.; Zhang, Q. Antitumor activity of dichloroacetate
on C6 glioma cell: in vitro and in vivo evaluation. Onco
Targets Ther., 2013, 6, 189-198.
[71] Lin, G.; Hill, D.K.; Andrejeva, G.; Boult, J.K.; Troy, H.;
Fong, A.C.; Orton, M.R.; Panek, R.; Parkes, H.G.; Jafar,
M.; Koh, D.M.; Robinson, S.P.; Judson, I.R.; Griffiths, J.R.;
Leach, M.O.; Eykyn, T.R.; Chung, Y.L. Dichloroacetate in-
duces autophagy in colorectal cancer cells and tumours. Br
J Cancer, 2014, 111(2), 375-385.
[72] Kim, K.Y.; Yu, S.N.; Lee, S.Y.; Chun, S.S.; Choi, Y.L.;
Park, Y.M.; Song, C.S.; Chatterjee, B.; Ahn, S.C. Salino-
mycin-induced apoptosis of human prostate cancer cells due
to accumulated reactive oxygen species and mitochondrial
membrane depolarization. Biochem Biophys Res Commun.,
2011, 413(1), 80-86.
[73] Zhu, L.Q.; Zhen, Y.F.; Zhang, Y.; Guo, Z.X.; Dai, J.;
Wang, X.D. Salinomycin activates AMP-activated protein
kinase-dependent autophagy in cultured osteoblastoma
cells: a negative regulator against cell apoptosis. PLoS One,
2013, 8(12), e84175.
[74] Leskovar, A.; Wegele, H.; Werbeck, N. D.; Buchner, J.;
Reinstein, J. The ATPase cycle of the mitochondrial Hsp90
analog Trap1. J. Biol. Chem., 2006, 283, 11677-11688.
[75] Kang, B. H.; Altieri, D. C. Compartmentalized cancer drug
discovery targeting mitochondrial Hsp90 chaperones. On-
cogene, 2009, 28, 3681-3688.
[76] Pridgeon, J. W.; Olzmann, J. A.; Chin, L. S.; Li, L. PINK1
protects against oxidative stress by phosphorylating mito-
chondrial chaperone TRAP1. PLoS Biol., 2007, 5, e172.
[77] Montesano, G. N.; Chirico, G.; Pirozzi, G.; Costantino, E.;
Landriscina, M.; Esposito, F. Tumor necrosis factor-
associated protein 1 (TRAP-1) protects cells from oxidative
stress and apoptosis. Stress, 2007, 10, 342-350.
[78] Yan, C.; Oh, J.S.; Yoo, S.H.; Lee, J.S.; Yoon, Y.G.; Oh,
Y.J.; Jang, M.S.; Lee, S.Y.; Yang, J.; Lee, S.H.; Kim, H.Y.;
Yoo, Y.H. The targeted inhibition of mitochondrial Hsp90
overcomes the apoptosis resistance conferred by Bcl-2 in
Hep3B cells via necroptosis. Toxicol Appl Pharmacol.,
2013, 266(1), 9-18.
12 Current Medicinal Chemistry, 2015, Vol. 22, No. 1
[79] Fulda, S.; Galluzzi, L.; Kroemer, G. Targeting mitochondria
for cancer therapy. Nat. Rev. Drug Discov., 2009, 9, 447-
464.
[80] Rico-Bautista, E.; Zhu, W.; Kitada, S.; Ganapathy, S.; Lau,
E.; Krajewski, S.; Ramirez, J.; Bush, J.A.; Yuan, Z.; Wolf,
D.A. Small molecule-induced mitochondrial disruption di-
rects prostate cancer inhibition via UPR signaling. Onco-
target, 2013, 4(8), 1212-1229.
[81] Rico-Bautista, E.; Yang, C.C.; Lu, L.; Roth, G.P.; Wolf,
D.A. Chemical genetics approach to restoring p27Kip1 re-
veals novel compounds with antiproliferative activity in
prostate cancer cells. BMC Biol., 2010, 8, 153.
[82] Chen, S.; Sun, L.; Koya, K.; Tatsuta, N.; Xia, Z.; Korbut,
T.; Du, Z.; Wu, J.; Liang, G.; Jiang, J.; Ono, M.; Zhou, D.;
Sonderfan, A. Syntheses and antitumor activities of
N'1,N'3-dialkyl-N'1,N'3-di-(alkylcarbonothioyl) malonohy-
drazide: the discovery of elesclomol. Bioorg Med Chem
Lett., 2013, 23(18), 5070-5076.
[83] Kirshner, J.R.; He, S.; Balasubramanyam, V. Elesclomol
induces cancer cell apoptosis through oxidative stress. Mol
Cancer Ther., 2008, 7(8): 2319-2327.
[84] Qu, Y.; Wang. J.; Sim, M.S.; Liu, B.; Giuliano, A.; Bar-
soum, J.; Cui, X. Elesclomol, counteracted by Akt survival
signaling, enhances the apoptotic effect of chemotherapy
drugs in breast cancer cells. Breast Cancer Res. Treat.,
2010, 121(2), 311-321.
[85] Yadav, A.A.; Patel, D.; Hasinoff , B.B. Molecular mecha-
nisms of the biological activity of the anticancer drug eles-
clomol and its complexes with Cu(II), Ni(II) and Pt(II)". J
Inorg Biochem., 2013, 126, 1-6.
[86] Horton, K.L.; Stewart, K.M.; Fonseca, S.B.; Guo, Q.; Kel-
ley, S.O. Mitochondria-penetrating peptides. Chem Biol.,
2008, 15(4), 375-382.
[87] Kelley, S.O.; Stewart, K.M.; Mourtada, R. Development of
novel peptides for mitochondrial drug delivery: amino acids
featuring delocalized lipophilic cations. Pharm Res., 2011,
28(11), 2808-2819.
[88] Horton, K.L.; Pereira, M.P.; Stewart, K.M.; Fonseca, S.B.;
Kelley, S.O. Tuning the activity of mitochondria-
penetrating peptides for delivery or disruption. Chembio-
chem., 2012; 13(3), 476-485.
[89] Prezma, T.; Shteinfer, A.; Admoni, L.; Raviv, Z.; Sela, I.;
Levi, I.; Shoshan-Barmatz, V. VDAC1-based peptides:
novel pro-apoptotic agents and potential therapeutics for B-
cell chronic lymphocytic leukemia. Cell Death Dis., 2013,
4, e809.
[90] Blatt, N.B.; Boitano, A.E.; Lyssiotis, C.A.; Opipari, A.W.
Jr.; Glick, G.D. Bz-423 superoxide signals apoptosis via se-
lective activation of JNK, Bak, and Bax. Free Radic Biol
Med., 2008, 45(9), 1232-1242.
[91] Giorgio, V.; von Stockum, S.; Antoniel, M.; Fabbro, A.;
Fogolari, F.; Forte, M.; Glick, G.D.; Petronilli, V.; Zoratti,
M.; Szab, I.; Lippe, G.; Bernardi, P. Dimers of mitochon-
drial ATP synthase form the permeability transition pore.
Proc Natl Acad Sci U S A., 2013, 110(15), 5887-5892.
[92] Sheu, S.S.; Nauduri, D.; Anders, M.W. Targeting antioxi-
dants to mitochondria: a new therapeutic direction. Biochim
Biophys Acta., 2006, 1762(2), 256-265.
[93] Smith, R.A.; Hartley, R.C.; Cochem, H.M.; Murphy, M.P.
Mitochondrial pharmacology. Trends Pharmacol Sci., 2012,
33(6), 341-352.
[94] Benrahmoune, M.; Thrond, P.; Abedinzadeh, Z. The reac-
tion of superoxide radical with N-acetylcysteine. Free
Radic Biol Med., 2000, 29(8), 775-782.
[95] Slyshenkov, V.S.; Dymkowska, D.; Wojtczak, L. Pantoth-
enic acid and pantothenol increase biosynthesis of glu-
tathione by boosting cell energetics. FEBS Lett., 2004,
569(1-3), 169-172.
Lyakhovich and Graifer
[96] Sharma, R.A.; Gescher, A.J.; Steward, W.P. Curcumin: the
story so far. Eur J Cancer, 2005, 41(13), 1955-1968.
[97] KC, S.; Crcamo, J.M.; Golde, D.W. Vitamin C enters mi-
tochondria via facilitative glucose transporter 1 (Glut1) and
confers mitochondrial protection against oxidative injury.
FASEB J., 2005, 19(12), 1657-1667.
[98] Liu, Y.; Dai, C.; Gao, R.; Li, J. Ascorbic acid protects
against colistin sulfate-induced neurotoxicity in PC12 cells.
Toxicol Mech Methods, 2013, 23(8), 584-590.
[99] Sliwa, A.; Gralska, J.; Czech, U.; Gruca, A.; Polus, A.;
Zapaa, B.; Dembiska-Kie, A. Modulation of the human
preadipocyte mitochondrial activity by beta-carotene. Acta
Biochim Pol., 2012, 59(1), 39-41.
[100] Rochette, L.; Ghibu, S.; Richard, C.; Zeller, M.; Cottin, Y.;
Vergely, C. Direct and indirect antioxidant properties of -
lipoic acid and therapeutic potential. Mol Nutr Food Res.,
2013, 57(1), 114-125.
[101] Valdecantos, M.P.; Prez-Matute, P.; Quintero, P.;
Martnez, J.A. Vitamin C, resveratrol and lipoic acid actions
on isolated rat liver mitochondria: all antioxidants but dif-
ferent. Redox Rep., 2010, 15(5), 207-216.
[102] Salvemini, D.; Riley, D.P.; Cuzzocrea, S. SOD mimetics
are coming of age. Nat Rev Drug Discov., 2002, 1(5), 367-
374.
[103] Shibuta, S.; Kosaka, J.; Mashimo, T.; Fukuda, Y.; Yoshiya,
I. Nitric oxide-induced cytotoxicity attenuation by thiopen-
tone sodium but not pentobarbitone sodium in primary
brain cultures. Br J Pharmacol., 1998, 124(4), 804-810.
[104] Dogan, Z.; Yuzbasioglu, M.F.; Kurutas, E.B.; Yildiz, H.;
Coskuner, I.; Senoglu, N.; Oksuz, H.; Blbloglu, E. Thio-
pental improves renal ischemia-reperfusion injury. Ren
Fail., 2010, 32(3), 391-395.
[105] Ariyama, J.; Shimada, H.; Aono, M.; Tsuchida, H.; Hirai,
K.I. Propofol improves recovery from paraquat acute toxic-
ity in vitro and in vivo. Intensive Care Med., 2000, 26(7),
981-987.
[106] Prabhakar, H.; Bindra, A.; Singh, G.P.; Kalaivani, M. Pro-
pofol versus thiopental sodium for the treatment of refrac-
tory status epilepticus. Evid Based Child Health, 2013,
8(4),1488-1508.
[107] Ernster, L., Dallner, G. Biochemical, physiological and
medical aspects of ubiquinone function. Biochim Biophys
Acta., 1995, 1271(1), 195-204.
[108] Crofts, A.R.; Hong, S.; Wilson, C.; Burton, R.; Victoria, D.;
Harrison, C.; Schulten, K. The mechanism of ubihydroqui-
none oxidation at the Qo-site of the cytochrome bc1 com-
plex. Biochim Biophys Acta., 2013, 1827(11-12), 1362-
1377.
[109] Bolognesi, M.L.; Matera, R.; Minarini, A.; Rosini, M.;
Melchiorre, C. Alzheimer's disease: new approaches to drug
discovery. Curr Opin Chem Biol., 2009, 13(3), 303-308.
[110] Naia, L.; Ribeiro, M.J.; Rego, A.C. Mitochondrial and
metabolic-based protective strategies in Huntington's dis-
ease: the case of creatine and coenzyme Q. Rev Neurosci.,
2011, 23(1), 13-28.
[111] Ebadi, M.; Govitrapong, P.; Sharma, S.; Muralikrishnan,
D.;, Shavali, S.; Pellett, L.; Schafer, R.; Albano, C.; Eken, J.
Ubiquinone (coenzyme q10) and mitochondria in oxidative
stress of parkinson's disease. Biol Signals Recept., 2001,
10(3-4), 224-253.
[112] Cleren, C.; Yang, L.; Lorenzo, B.; Calingasan, N.Y.;
Schomer, A.; Sireci, A.; Wille, E.J.; Beal, M.F. Therapeutic
effects of coenzyme Q10 (CoQ10) and reduced CoQ10 in
the MPTP model of Parkinsonism. J Neurochem., 2008,
104(6), 1613-1621.
[113] Orsucci, D.; Mancuso, M.; Ienco, E.C.; LoGerfo, A.; Sicil-
iano, G. Targeting mitochondrial dysfunction and neurode-
Drugs Targeting Oxidative Stress in Mitochondria
generation by means of coenzyme Q10 and its analogues.
Curr Med Chem., 2011, 18(26), 4053-4064.
[114] James, A.M.; Smith, RA.; Murphy, M.P. Antioxidant and
prooxidant properties of mitochondrial Coenzyme Q. Arch
Biochem Biophys., 2004, 423(1), 47-56.
[115] Liberman, E.A.; Topaly, V.P.; Tsofina, L.M.; Jasaitis, A.A.;
Skulachev, V.P. Mechanism of coupling of oxidative phos-
phorylation and the membrane potential of mitochondria.
Nature, 1969, 222(5198), 1076-1078.
[116] Filipovska, A.; Kelso, G.F.; Brown, S.E.; Beer, S.M.;
Smith, R.A.; Murphy, M.P. Synthesis and characterization
of a triphenylphosphonium- ubiquinonyl-decyl-
triphenylphosphonium (MitoQ) conjugated peroxidase mi-
metic. Insights into the interaction of ebselen with mito-
chondria. J Biol Chem., 2005, 280(25), 24113-24126.
[117] Brown, S.E.; Ross, M.F.; Sanjuan-Pla, A.; Manas, A.R.;
Smith, R.A.; Murphy, M.P. Targeting lipoic acid to mito-
chondria: synthesis and characterization of a triphenylphos-
phonium-conjugated alpha-lipoyl derivative. Free Radic
Biol Med., 2007, 42(12), 1766-1780.
[118] Cunniff, B.; Benson, K.; Stumpff, J.; Newick, K.; Held, P.;
Taatjes, D.; Joseph, J.; Kalyanaraman, B., Heintz, N.H. Mi-
tochondrial-targeted nitroxides disrupt mitochondrial archi-
tecture and inhibit expression of peroxiredoxin 3 and
FOXM1 in malignant mesothelioma cells. J Cell Physiol.,
2013, 228(4), 835-845.
[119] Cheng, G.; Lopez, M.; Zielonka, J.; Hauser, A.D.; Joseph,
J.; McAllister, D.; Rowe, J.J.; Sugg, S.L.; Williams, C.L.;
Kalyanaraman, B. Mitochondria-targeted nitroxides exacer-
bate fluvastatin-mediated cytostatic and cytotoxic effects in
breast cancer cells. Cancer Biol Ther., 2011, 12(8), 707-
717.
[120] Tauskela, J.S. MitoQ--a mitochondria-targeted antioxidant.
IDrugs, 2007, 10(6), 399-412.
[121] Severin, F.F.; Severina, I.I.; Antonenko, Y.N.; Rokitskaya,
T.I.; Cherepanov, D.A.; Mokhova, E.N.; Vyssokikh, M.Y.;
Pustovidko, A.V.; Markova, O.V.; Yaguzhinsky, L.S.; Kor-
shunov G.A.; Sumbatyan, N.V.; Skulachev, M.V.; Sku-
lachev, V.P. Penetrating cation/fatty acid anion pair as a mi-
tochondria-targeted protonophore. Proc Natl Acad Sci U S
A, 2010, 107(2), 663-668.
[122] Skulachev, V.P.; Anisimov, V.N.; Antonenko, Y.N.;
Bakeeva, L.E.; Chernyak, B.V.; Erichev, V.P., Filenko,
O.F., Kalinina, N.I., Kapelko, V.I., Kolosova, N.G., Kop-
nin, B.P.; Korshunova, G.A.; Lichinitser, M.R.; Obukhova,
L.A.; Pasyukova, E.G.; Pisarenko, O.I.; Roginsky, V.A.;
Ruuge, E.K.; Senin, I.I.; Severina, I.I.; Skulachev, M.V.;
Spivak, I.M.; Tashlitsky, V.N.; Tkachuk, V,A.; Vyssokikh,
M.Y.; Yaguzhinsky, L.S.; Zorov, D.B. An attempt to pre-
vent senescence: a mitochondrial approach. Biochim Bio-
phys Acta., 2009, 1787(5), 437-461.
[123] Gruber, J.; Fong, S.; Chen, C.B.; Yoong, S.; Pastorin, G.;
Schaffer, S.; Cheah, I.; Halliwell, B. Mitochondria-targeted
antioxidants and metabolic modulators as pharmacological
interventions to slow ageing. Biotechnol Adv., 2013, 31(5),
563-592.
[124] Ajith, T.A.; Jayakumar, T.G. Mitochondria-targeted agents:
Future perspectives of mitochondrial pharmaceutics in car-
diovascular diseases. World J Cardiol., 2014, 6(10), 1091-
1099.
[125] Szeto, H.H. Cell-permeable, mitochondrial-targeted, pep-
tide antioxidants. AAPS J., 2006, 8(2), E277-E283.
[126] Valero, T. Mitochondrial biogenesis: pharmacological ap-
proaches. Curr Pharm Des., 2014, 20(35), 5507-5509.
[127] Kumaran, S.; Subathra, M.; Balu, M.; Panneerselvam, C.
Age-associated decreased activities of mitochondrial elec-
tron transport chain complexes in heart and skeletal muscle:
Current Medicinal Chemistry, 2015, Vol. 22, No. 1 13
role of L-carnitine. Chem Biol Interact., 2004, 148(1-2), 11-
18.
[128] Ye, J.; Li, J.; Yu, Y.; Wei, Q.; Deng, W.; Yu, L. L-carnitine
attenuates oxidant injury in HK-2 cells via ROS-
mitochondria pathway. Regul Pept., 2010, 161(1-3), 58-66.
[129] Wu, J.; Niu, J.; Li, X.; Wang, X.; Guo, Z.; Zhang. F. TGF-
1 induces senescence of bone marrow mesenchymal stem
cells via increase of mitochondrial ROS production. BMC
Dev Biol., 2014, 14, 21.
[130] Rucker, R.; Chowanadisai, W.; Nakano, M. Potential
physiological importance of pyrroloquinoline quinone. Al-
tern Med Rev., 2009, 14(3), 179-183.
[131] Vos, M.; Esposito, G.; Edirisinghe, J.N.; Vilain, S.; Had-
dad, D.M.; Slabbaert, J.R.; Van Meensel, S.; Schaap, O.; De
Strooper, B.; Meganathan, R.; Morais, V.A.; Verstreken, P.
Vitamin K2 is a mitochondrial electron carrier that rescues
pink1 deficiency. Science, 2012, 336(6086), 1306-1310.
[132] Sai Varsha, M.K.; Raman, T.; Manikandan, R. Inhibition of
diabetic-cataract by vitamin K1 involves modulation of hy-
perglycemia-induced alterations to lens calcium homeosta-
sis. Exp Eye Res., 2014, 128, 73-82.
[133] Pan, R.; Rong, Z.; She, Y.; Cao, Y.; Chang, L.W.; Lee,
W.H. Sodium pyruvate reduces hypoxic-ischemic injury to
neonatal rat brain. Pediatr Res., 2012, 72(5), 479-489.
[134] Simeone, K.A.; Matthews, S.A.; Samson, K.K.; Simeone,
T.A. Targeting deficiencies in mitochondrial respiratory
complex I and functional uncoupling exerts anti-seizure ef-
fects in a genetic model of temporal lobe epilepsy and in a
model of acute temporal lobe seizures. Exp Neurol., 2014,
251, 84-90.
[135] Rambo, L.M.; Ribeiro, L.R.; Della-Pace, I.D.; Stamm,
D.N.; da Rosa Gerbatin, R., Prigol, M.; Pinton, S.; No-
gueira, C.W.; Furian, A.F.; Oliveira, M.S.; Fighera, M.R.;
Royes, L.F. Acute creatine administration improves mito-
chondrial membrane potential and protects against pentyle-
netetrazol-induced seizures. Amino Acids, 2013, 44(3), 857-
868.
[136] Webster, I.; Du Toit E.F.; Huisamen, B.; Lochner, A. The
effect of creatine supplementation on myocardial function
and mitochondrial respiration to ischaemia/reperfusion in-
jury in sedentary and exercised rats. Acta Physiol (Oxf).,
2012, 206(1), 6-19.
[137] Ribeiro, M.; Silva, A.C.; Rodrigues, J.; Naia, L.; Rego,
A.C. Oxidizing effects of exogenous stressors in
Huntington's disease knock-in striatal cells--protective ef-
fect of cystamine and creatine. Toxicol Sci., 2013, 136(2),
487-499.
[138] Schls, L.; Vorgerd, M.; Schillings, M.; Skipka, G.; Zange,
J. Idebenone in patients with Friedreich ataxia. Neurosci
Lett., 2001, 306(3), 169-172.
[139] Garca-Gimnez, J.L.; Gimeno, A.; Gonzalez-Cabo, P.,
Das, F.; Bolinches-Amors, A.; Moll, B.; Palau, F.; Pal-
lard, F.V. Differential expression of PGC-1 and meta-
bolic sensors suggest age-dependent induction of mito-
chondrial biogenesis in Friedreich ataxia fibroblasts. PLoS
One, 2011, 6(6), e20666.
[140] Garrel, C.; Alessandri, J.M.; Guesnet, P.; Al-Gubory, K.H.
Omega-3 fatty acids enhance mitochondrial superoxide
dismutase activity in rat organs during post-natal develop-
ment. Int J Biochem Cell Biol., 2012, 44(1), 123-131.
[141] Zugno, A.I.; Chipindo, H.L.; Volpato, A.M.; Budni, J.;
Steckert, A.V.; de Oliveira, M.B.; Heylmann, A.S.; da Rosa
Silveira, F.; Mastella, G.A.; Maravai, S.G.; Wessler, P.G.;
Binatti, A.R.; Panizzutti, B.; Schuck, P.F.; Quevedo, J.;
Gama, C.S. Omega-3 prevents behavior response and brain
oxidative damage in the ketamine model of schizophrenia.
Neuroscience, 2014, 259, 223-231.
14 Current Medicinal Chemistry, 2015, Vol. 22, No. 1
[142] Kones, R. Mitochondrial therapy for Parkinson's disease:
neuroprotective pharmaconutrition may be disease-
modifying. Clin Pharmacol., 2010, 2, 185-198.
[143] Kang, J.X. From fat to fat-1: a tale of omega-3 fatty acids. J
Membr Biol., 2005, 206(2), 165-172.
[144] Romanatto, T.; Fiamoncini, J.; Wang, B.; Curi, R.; Kang,
J.X. Elevated tissue omega-3 fatty acid status prevents age-
related glucose intolerance in fat-1 transgenic mice. Bio-
chim. Biophys. Acta., 2014, 1842(2), 186-191.
[145] Rodrigo, R.; Prieto, J.C.; Castillo, R. Cardioprotection
against ischaemia/reperfusion by vitamins C and E plus n-3
fatty acids: molecular mechanisms and potential clinical
applications. Clin. Sci. (Lond), 2013, 124(1), 1-15.
Received: February 26, 2015 Revised: July 14, 2015 Accepted: July 26, 2015
Lyakhovich and Graifer
[146] Segal, A.W. How neutrophils kill microbes. Annu. Rev.
Immunol., 2005, 9(5), 197-223.
[147] Ray, P.D., Huang, B.W., Tsuji, Y. Reactive oxygen species
(ROS) homeostasis and redox regulation in cellular signal-
ing. Cell Signal, 2012, 24(5), 981-990.
[148] Ryter, S.W., Kim, H.P., Hoetzel, A., Park, J.W., Nakahira,
K., Wang, X., Choi, A.M. Mechanisms of cell death in oxi-
dative stress. Antioxid Redox Signal, 2007, 9(1), 49-89.
[149] Rhee, S. G. Cell signaling: H2O2, a Necessary Evil for Cell
Signaling. Science, 2006, 312(5782), 1882-1883.
[150] Gugger, M., Waser, B., Kappeler, A., Schonbrunn, A.,
Reubi, J.C. Cellular detection of sst2A receptors in human
gastrointestinal tissue. Gut, 2004, 53(10):1431-1436.