cells
Re iew
Role o Mi ochond ia in Cance S em Cell Resis ance
JoséManuel Ga cía-He edia 1,2,3,* and Amancio Ca ne o 1,3,*
1Ins i u o de Biomedicina de Se illa (IBIS), Hospi al Uni e si a io Vi gen del Rocío, Uni e sidad de Se illa,
Consejo Supe io de In es igaciones Cien í icas, A da. Manuel Siu o s/n, 41013 Se ille, Spain
2Depa amen o de Bioquímica Vege al y Biología Molecula , Facul ad de Biología, Uni e sidad de Se illa,
A da. de la Reina Me cedes 6, 41012 Se ille, Spain
3Cen o de In es igación Biomédica en Red de Cánce , CIBERONC, Ins i u o de Salud Ca los III,
28029 Mad id, Spain
*
Co espondence: jmghe [email p o ec ed] (J.M.G.-H.); [email p o ec ed] (A.C.); Tel.: +34-955-923-115 (J.M.G.-H.);
+34-955-923-110 (A.C.)
Recei ed: 4 June 2020; Accep ed: 15 July 2020; Published: 15 July 2020

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Abs ac :
Cance s em cells (CSC) a e associa ed wi h he mechanisms o chemo esis ance o di e en
cy o oxic d ugs o adio he apy, as well as wi h umo elapse and a poo p ognosis. Va ious s udies
ha e shown ha mi ochond ia play a cen al ole in hese p ocesses because o he abili y o his
o ganelle o modi y cell me abolism, allowing su i al and a oiding apop osis clea ance o cance
cells. Thus, he whole mi ochond ial cycle, om i s biogenesis o i s dea h, ei he by mi ophagy
o by apop osis, can be a ge ed by di e en d ugs o educe mi ochond ial i ness, allowing o
a es o ed o inc eased sensi i i y o chemo he apeu ic d ugs. Once mi ochond ial misbalance is
induced by a speci ic d ug in any o he p ocesses o mi ochond ial me abolism, wo elemen s a e
commonly boos ed: an inc emen in eac i e ni ogen/oxygen species and, subsequen ly, ac i a ion o
he in insic apop o ic pa hway.
Keywo ds: cance s em cells; mi ochond ia; d ug esis ance; me abolic plas ici y
1. In oduc ion
Tumo s and hei mic oen i onmen cons i u e a e y he e ogeneous s uc u e, wi h mul iple
pheno ypes ha make hem i ually me abolic ecosys ems, di e en om s uc u es in o he pa s o
he body. These he e ogeneous s uc u es, in addi ion o di e en umo cell ypes, comp ise s omal
cells such as in il a ed ib oblas s, endo helial cells and immune cells [
1
–
3
]. These non- umo cells can
g ea ly in luence he plas ici y and unc ionali y o umo cells [
1
,
4
]. Fu he mo e, wi hin he umo
cell popula ion, g ea he e ogenei y exis s, a ising om bo h gene ic and epigene ic di e ences [
3
,
5
].
Al hough umo s a e la gely clonal de i a i es o a single cell, bo h he genomic ins abili y o
umo cells and mic oen i onmen a ia ions make umo cells a e y he e ogeneous popula ion [
5
].
This he e ogenei y allows cance cells o adap o di e en s esses ha could appea in he umo
mic oen i onmen , such as in lamma ion, hypoxia, low pH and nu ien s. Thus, ei he di e en umo
cells o di e en cell me abolism p ope ies can be ound wi hin a umo wi h inc easing a iabili y,
which inc eases he p obabili y ha a umo can su i e and in ade o he issues [6,7].
Mos umo cells a e conside ed di e en ia ed— ha is, unable o egene a e a umo by hemsel es
o me as asize—cons i u ing he bulk o he umo mass [
8
,
9
]. In il a ed among hem, a small
pe cen age, gene ally less han 1–2% o he o al, exhibi s s em cell cha ac e is ics [
9
,
10
]. These cells
we e ini ially iden i ied in leukemia (AML), bu cance s em cells (CSCs) ha e also been ound in b eas ,
lung, colon, b ain, head and neck, p os a e o li e umo s, among o he s [
11
,
12
]. These CSCs, also
called s em-likecance cells, umo -ini ia ing cells (TICs)o cance -ini ia ing cells, a e conside ed oha e
he highes associa ed isk due o hei abili y o bo h sel - enewal and umo ini ia ion
in i o
, as well
Cells 2020,9, 1693; doi:10.3390/cells9071693 www.mdpi.com/jou nal/cells
Cells 2020,9, 1693 2 o 28
as hei abili y o in ade and mig a e o o he issues, leading o me as asis [
13
–
15
]. These cells, which
ha e a low p oli e a ion a e, a e he only cells wi hin a umo capable o gene a ing umo cells wi h
di e en cha ac e is ics, an a ibu e sha ed wi h s em cells. Thus, umo s may a ise due o mu a ions
ha occu in no mal s em cells o om di e en ia ed cells ha acqui e s em-like ea u es [
16
,
17
]. Thus,
an abno mal inc ease in gene ansc ip ion ela ed o s em cell egula o y pa hways, such as c-MYC,
Bmi-1, Hedgehog, No ch and Wn , has been obse ed in CSC popula ions [
18
,
19
]. Simila ly, s ess
condi ions in he umo mic oen i onmen , ypically wi h low oxygen le els and a limi ed nu ien
supply, p omo e he epi helial- o-mesenchymal ansi ion (EMT), leading o inc eased sel - enewal
and cell mig a ion [7,13,20].
CSCs ha e been shown o be esis an o commonly used chemo he apeu ic agen s in leukemia,
malignan melanoma, and b ain, head and neck, b eas , panc eas and colo ec al umo s [
21
–
27
].
Simila ly, b ain and b eas umo s ha e also shown esis ance o adia ion he apy [
28
,
29
]. Thus, CSCs
a e esponsible o umo elapse in many umo ypes because hey can esis cance he apies, ei he
in insically o because o changes a ising om ea men . The ela i e abundance o CSCs is associa ed
wi h he clinical ou come [
30
]. Thus, al hough adi ional chemo he apy and adio he apy can emo e
mos umo cells, CSCs a e hough o su i e, de eloping esis ance du ing ea men [
18
,
20
,
26
,
31
,
32
]. Consequen ly, hese cells emain hidden in he body o he pa ien s un il i s eac i a ion [
33
],
egene a ing he umo o mig a ing o o he o gans o me as asize. This makes hem an a ac i e
a ge o design new cance he apies, because con en ional ea men s can kill, by au ophagy and
apop osis, mos o he umo , bu do no a ec CSCs [
13
,
14
,
28
,
34
,
35
]. This ac inc eases he CSC
popula ion and causes a mo e agg essi e umo elapse [
14
,
15
,
26
]. The cellula mechanisms unde lying
his pheno ype o d ug esis ance emain la gely unknown, al hough he e a e some common elemen s,
including he ollowing:
—Cell quiescence, ha is, a s a e in which CSCs do no di ide, o do so e y slowly [
13
,
15
,
27
,
36
,
37
].
Quiescence p ope ies, such as main enance in he G0/G1 s age in s em cells, p o ec hem om
cy o oxic s ess [
38
]. Mos chemo he apeu ic d ugs a e based on umo cells di iding as e han
no mal cells, p oducing li le o no e ec on CSCs [39];
—O e exp ession o d ug anspo e s ha allow an ac i e ou low o he d ug [
40
–
42
]. Thus,
he ABC genes cons i u e a b oad amily o ATP-dependen anspo e s in which a leas 16 o hem
ha e been linked o esis ance o an icance d ugs [
43
]. Mo eo e , a simila pheno ype is caused by
he loss o cell su ace ecep o s o anspo e s ha allow he d ug o en e he cell [14,44];
—An inc ease in he le els o exp ession o he molecula a ge s o chemo he apeu ic d ugs,
which causes, consequen ly, a dec ease in e ec i eness [
44
,
45
], ha can be achie ed, in a simila way, by
he accumula ion o chemo he apeu ic d ugs in in acellula esicles, educing i s biological e ec [
46
];
—Inc eased abili y o epai DNA damage [
28
,
42
]. T ea men wi h chemo he apeu ic d ugs, such
as cispla in o ca bopla in, can induce apop o ic dea h in sensi i e cance cells h ough he accumula ion
o DNA damage, eaching a le el ha makes epai impossible;
—O e exp ession o an iapop o ic p o eins o educed exp ession o p o eins ela ed o
apop osis [
47
,
48
]. Ce ain CSCs exhibi ed highe exp ession le els o p osu i al p o eins om
he BCL-2 amily [49];
—Resis ance o eac i e ni ogen and oxygen species (RNOS) [
14
,
15
,
35
,
36
]. Many d ugs
p oduce RNOS in excess, usually gene a ing DNA damage and modi ying p o ein unc ionali y,
igge ing apop osis;
—De egula ion o au ophagy [
13
,
34
,
42
], he p ocess in which double-memb ane esicles
(au ophagosomes) encompass di e en pa s o he cell, including o ganelles, allowing he ecycling o
i s componen s a e usion wi h he lysosome. This p ocess is highly ela ed o he main enance o
CSCs bu is no es ic ed o hem. In cance -associa ed ib oblas s (CAFs), an inc ease in au ophagy
has been obse ed, inc easing he nu ien s ecei ed by umo cells [
3
,
4
]. CAFs also p o ide cy okines
ha s imula e mi ochond ial biogenesis in cance cells [
50
]. Likewise, an inc emen in mi ochond ial
Cells 2020,9, 1693 3 o 28
au ophagy (mi ophagy) educes oxida i e me abolism, making umo cells dependen on glycolysis and
less e icien in gene a ing ATP and a o ing a slow cell cycle, ypical o some s em cells [
13
,
14
,
34
,
35
,
51
].
—Me abolicchanges. Mos CSCs exhibi highme abolic plas ici y, whichwould acili a e heabili y
o hese cells o h i e in ad e se mic oen i onmen al condi ions, such as hose o hypoxia ha usually
exis in umo s [
6
,
18
,
35
,
36
]. This me abolic plas ici y would allow hem o modi y hei me abolism
om oxida i e espi a ion o ae obic glycolysis. In his way, and e en wi hin he same umo , CSCs
wi h glycoly ic and oxida i e me abolism can coexis , in addi ion o di e en ia ed cells wi h di e en
me abolic pheno ypes, because o di e en gene ic o mic oen i onmen al ac o s [
52
,
53
]. Addi ionally,
o he me aboli es, such as a y acids, ke ones o amino acids, can be used by cance cells o suppo
me abolism [
6
,
35
,
54
]. Due o he c ucial con ibu ion o me abolism in malignan ans o ma ion and
umo p og ession, me abolic ep og amming/plas ici y has become one o he cha ac e is ics o cance .
Many o hese pa hways a e media ed by edox imbalance and he in ol emen o ROS
de oxi ica ion sys ems, which usually show CSCs in ol ed in he up egula ion o ROS me abolism [
14
,
55
]. In his way, umo cells can modula e di e en me abolic pa hways o ob ain ene gy and di e en
me aboli es, while also main aining edox balance. In many o hese p ocesses, he mi ochond ia play
an essen ial ole. Thus, hey a e esponsible o he syn hesis o many me aboli es, pa icipa ing ac i ely
in apop o ic mechanisms, in addi ion o being he bioene ge ic powe s a ion o he cell and whe e
mos in acellula ROS a e p oduced and elimina ed [
52
,
53
]. Thus, in some CSCs, an inc ease was
obse ed in he ansc ip ion o nuclea genes ha encode mi ochond ial p o eins [
56
,
57
]. These esul s
sugges ha ce ain CSCs depend on bo h me abolism and mi ochond ial biogenesis o hei su i al
and sp ead. Th oughou his e iew, we will ocus on he ole o mi ochond ia in he mechanisms o
CSC esis ance o di e en d ugs, as well as in possible s a egies ha enable he ci cum en ion o
hese mechanisms.
2. Mi ochond ia as a C ucial Elemen in Cance
Mi ochond ia pe o m an essen ial unc ion in cells by coo dina ing bo h he p oduc ion and
dis ibu ion o ene gy h ough oxida i e phospho yla ion (OXPHOS) based on oxygen and subs a e
a ailabili y. I also ca ies ou o he impo an me abolic eac ions, such as he ci ic acid o ica boxylic
acid (TCA) cycle, a y acid oxida ion (FAO) o glu aminolysis. Due o i s ole in essen ial cellula
unc ion, his o ganelle has been linked o mul iple aspec s o umo igenesis and umo p og ession [
58
].
In many me abolic pa hways in which mi ochond ia a e in ol ed, al e a ions ha e been ound in
umo cells and, speci ically, in CSCs [
35
,
53
,
54
,
59
,
60
]. Consequen ly, mul iple chemo he apeu ic d ugs
a ge mi ochond ia, ei he di ec ly o h ough pa hways egula ing mi ochond ial ac i i y. This u ns
d ugs ha a ge mi ochond ia in o p omising agen s o in e e e wi h umo adap a ions, allowing
he elimina ion o CSCs [
61
]. I is impo an o conside ha mi ochond ia do no play a unique ole
in umo igenesis and umo p og ession o he esponse o umo cells o ea men s. Depending on
he issue in which he umo appea s, he e will be epigene ic o umo mic oen i onmen di e ences
ha can modi y mi ochond ial unc ionali y [
5
,
54
,
59
]. E en wi hin he same umo , di e ences
be ween cells can mean di e ences in mi ochond ial unc ionali y o me abolism, hus p omo ing
umo adap a ion o i s mic oen i onmen and he esis ance capaci y o he cells.
We mus conside he cell as a whole so ha modi ica ions in an o ganelle will ha e side
e ec s in o he pa s o he cell. To illus a e his, we can conside he di ec communica ion
be ween mi ochond ia and he nucleus, called he e og ade esponse, which sugges s ha changes
in mi ochond ial physiology o me abolism may induce changes in gene exp ession [
51
,
52
,
54
,
57
].
Thus, he NAD
+
/NADH a io, le els o ace yl-CoA, ATP, ROS o speci ic mi ochond ial me aboli es
a e in ol ed in his p ocess [
62
]. Fu he mo e, because mos o he p o eins ha play a ole in
he mi ochond ia a e encoded in he nucleus, he e is a equi ed nucleo-mi ochond ia communica ion
o allow no only he p ope mi ochond ial unc ion bu also he eplica ion o mi ochond ial DNA
(m DNA) h ough he impo in o mi ochond ia o p o eins such as TFAM, POLG and POLGY2 [
52
,
63
].
Cells 2020,9, 1693 4 o 28
Mul iple signaling pa hways can modi y mi ochond ial unc ion, such as he PI3K/AKT/mTOR
pa hway, wi h mul iple oles in umo igenesis [
64
]. This ac makes i challenging o desc ibe in
a e iew all he p ocesses implied in CSCs’ d ug esis ance media ed by mi ochond ia. Thus, he ein,
we will mainly ocus on mi ochond ial p ocesses. I we analyze he cycle o a mi ochond ion, h ee key
s eps a e in ol ed: he gene a ion o new mi ochond ia (biogenesis), mi ochond ial me abolism, and
he au ophagy o aging o non- unc ional mi ochond ia (mi ophagy) [
13
,
34
,
54
,
60
,
65
]. Fo each s ep,
CSCs exhibi esis ance mechanisms o di e en d ugs. To conside he mi ochond ial mechanisms o
CSC esis ance, he c oss alk be ween di e en p ocesses inside a cell mus be discussed. Mul iple
d ugs gene a e oxida i e s ess, inducing inc eased ROS, agains which he e a e mul iple de ense
mechanisms in mi ochond ia [
14
,
55
]. Al hough some d ugs cause DNA damage ha will p oduce
inc eased ROS, o he d ugs p oduce inc eased ROS ha will damage DNA [
66
,
67
]. Addi ionally,
mi ochond ia a e c ucial in cell dea h/su i al due o he ole o some o hei ela ed p o eins, such
as cy och ome c, in igge ing he in insic apop o ic pa hway [
68
]. Th oughou his e iew, we will
discuss how al e a ions in he egula ion o each o he h ee key s eps (biogenesis, me abolism and
mi ophagy) modi y he esis ance o CSCs o di e en chemo he apeu ic d ugs. In addi ion, we will
discuss how ha esis ance can be o e come, inducing apop o ic pa hway o umo cell clea ance.
3. Mi ochond ial Biogenesis and CSC Resis ance
Mi ochond ial biogenesis is a c ucial s ep in he main enance o he cell cycle and o co ec
me abolism. In all cells, mi ochond ia mus be syn hesized om a p e-exis ing one, an essen ial
s ep o co ec cell di ision [
65
]. Each cell con ains a a iable numbe o copies o mi ochond ial
DNA (m DNA), encoding 13 polypep ides essen ial o OXPHOS, as well as RNAs and RNAs,
wi h he emaining mi ochond ial p o eins encoded in he nuclea genome [
57
]. Thus, mi ochond ial
p o eins encoded by nuclea and mi ochond ial genes mus be ansc ibed in a coo dina ed way o
o m some o he mi ochond ial complexes associa ed wi h OXPHOS [
69
]. Inc eased mi ochond ial
biogenesis is usually connec ed wi h a highe umo igenic a e [
70
,
71
], which suppo s he main enance
o s em-like p ope ies in a ce ain popula ion o CSCs, independen ly o hei me abolism [
72
–
74
].
Thus, an inc eased mi ochond ial mass is usually de ec ed in CSCs, e lec ing inc eased mi ochond ial
biogenesis, which is also ela ed o inc eased chemo esis ance [
18
,
72
,
73
,
75
,
76
] (Figu e 1). Howe e ,
his is no a uni e sal e en because i has been also epo ed ha cells wi h inc eased mi ochond ial
biogenesis a e less glycoly ic and exhibi educed in asi e p ope ies [77].
Acco ding o endosymbio ic heo y and he bac e ial o igin o mi ochond ia, an ibio ics designed
o bac e ia also a ge mi ochond ia. This means ha some an ibio ics can be used o inhibi he sp ead
o CSCs. Among hese a e doxycycline ( e acycline), igecycline (glycylcycline), azi h omycin
(e y h omycin), an ipa asi ic d ugs (py inium pamoa e, a o aquone), and an imycobac e ial d ugs,
such as bedaquiline [
75
,
78
]. These d ugs ha e accep able side e ec s, which would allow hei use as
he apeu ic agen s o e adica e CSCs [
75
] (Figu e 1). Thus, doxycycline, igecycline and azi h omycin
inhibi p o ein ansla ion, which blocks mi ochond ial biogenesis [
73
,
75
,
79
,
80
]. Due o he high
numbe o mi ochond ia in many issues, such as he skele al muscle, b ain, and hea , no mal cells
would be sligh ly a ec ed by an ibio ic ea men . Howe e , mi ochond ial biogenesis is highe in
umo cells, wi h a highe mi ochond ial mass, making hem mo e sensi i e o hese an ibio ics. Clinical
ials wi h doxycycline and azi h omycin showed posi i e e ec s, such as inc eased pa ien su i al
and a educ ion in he pe cen age o CSCs in mul iple cance ypes [
81
,
82
]. Addi ionally, doxycycline
was shown o o e come pacli axel esis ance in CSCs [
79
] and educe he CSC popula ion in ea ly
b eas cance pa ien s [
81
]; addi ionally, i is a s ong adiosensi ize [
75
]. Fu he mo e, his d ug
could a ge pacli axel- esis an CSCs [
79
]. Howe e , con inuous ea men o cance wi h an ibio ics
may p o e ine ec i e in he long e m due o he appea ance o esis ance in cul u ed cells caused by
al e a ions in m DNA, such as i s educ ion (Figu e 1). In his way, doxycycline- esis an CSCs, wi h
lowe m DNA con en , exhibi ed an in lexible me abolism [
83
]. Thus, he cells, acco ding o glycolysis,
Cells 2020,9, 1693 5 o 28
a e mo e sensi i e o o he me abolic inhibi o s, such as Vi amin C, which has been desc ibed o block
ae obic glycolysis by a ge ing glyce aldehyde-3-phospha e dehyd ogenase (GAPDH) [84].
Figu e 1.
Mi ochond ial biogenesis misbalance in cance s em cells (CSCs). In no mal cells,
mi ochond ial mass is usually main ained. Howe e , bo h inc eased mi ochond ial biogenesis,
on he one hand, and al e a ions on m DNA, on he o he hand, a e connec ed wi h an inc eased
esis ance in CSCs. Black a ows e e o inc eased chemo esis ance, om a no mal si ua ion whe e
mi ochond ial biogenesis allows he main enance o mi ochond ial popula ion. T ea men wi h
an ibio ics o CSCs wi h high mi ochond ial biogenesis can o e come chemo esis ance ( ed a ow), bu
p olonged ea men s can o ce he appea ance o a CSC popula ion wi h educed m DNA (do ed
ed a ow).
To comple e co ec mi ochond ial biogenesis, m DNA mus be co ec ly main ained.
The mu a ional a e o he mi ochond ial genome is highe han ha exhibi ed by he nuclea
genome [
85
], wi h equen ly de ec ed mu a ions being associa ed wi h he appea ance o umo s [
86
]
(Figu e 1). Thus, m DNA damage can induce umo p og ession o an ad anced pheno ype in di e en
umo ypes [
57
]. The p esence o mu a ions in he mi ochond ial genome is common in umo s, wi h
equen esis ance o chemo he apeu ic agen s such as 5- luo ou acil (5-FU) and cispla in acili a ing
hese mu a ions’ esis ance o o he d ugs, such as ca bopla in, based on a simila p inciple o d ug
ac ion [
87
]. Damage o m DNA, o e en i s loss, causes a educ ion in he a e o cell p oli e a ion,
cha ac e is ic o CSCs [
39
,
52
]. Thus, la ge m DNA dele ions and a educed copy numbe o m DNA by
he cell a e usually associa ed wi h ad anced umo s, inc eased me as asis and a poo p ognosis [
52
,
57
].
Addi ionally, a low m DNA con en was de ec ed in up o 80% o b eas umo s [
88
]. These umo s
wi h low m DNA con en also induced EMT and an inc ease in in asi e and me as a ic p ope ies,
cons i u ing a mo e malignan pheno ype [
89
]. Fu he mo e, despi e poo me abolism, an i-apop o ic
and su i al pa hways a e ac i a ed by e og ade signaling om he mi ochond ia o he nucleus [
52
].
The e o e, hese ai s p oduce an inc ease in he popula ion o CSCs esis an o chemo he apeu ic
d ugs, such as inc is ine, doxo ubicin and pacli axel [
52
,
57
,
90
]. Thus, mi ochond ial-de icien cells
ha e shown esis ance o inc eased ROS le els, such as di ec ea men wi h hyd ogen pe oxide
o ROS-inducing agen s, such as doxo ubicin, pa aqua and menadione, possibly due o inc eased
exp ession le els o an ioxidan enzymes [
91
]. Simila ly, m DNA-deple ed cells also showed esis ance
o cispla in, hyd oxy amoxi en, pacli axel o TNF-induced apop osis in di e en cance cells [
90
,
92
,
93
].
Howe e , despi e he damage o m DNA, o e en i s absence, he mi ochond ial s uc u e, mainly
encoded in he nuclea genome, is necessa y o allow he CSC pheno ype. Indeed, non- umo cells wi h
m DNA-de icien mi ochond ia can esis s au ospo ine-media ed apop osis by inc eased exp ession

Cells 2020,9, 1693 6 o 28
o he an iapop o ic p o eins BCL-2 and BCL-XL, seques a ion o p oapop o ic ac o s (BID, BAX,
BAD) in he in e nal mi ochond ial memb ane and educed ac i a ion o caspases 3, 8 and 9, among
o he s p ope ies [
94
]. These esul s show ha , in gene al, he educ ion in m DNA con en is ela ed
o inc eased esis ance o di e en d ugs. Addi ionally, m DNA-deple ed mi ochond ia usually show
de ec i e mi ochond ial unc ion, wi h a common me abolic swi ch owa ds he Wa bu g e ec [
52
,
86
].
In e es ingly, cells wi h low m DNA le els exhibi ed lowe le els o he umo supp esso BRCA2,
becoming mo e sensi i e o PARP inhibi o s, p obably due o syn he ic le hali y [95,96].
Mi ochond ial biogenesis is inely uned by cells, wi h mul iple pa hways o egula o s, such as
PGC-1
α
, MYBBP1a o he MAPK/ERK pa hway, which can modi y hei ac i i y [
63
,
97
–
100
]. PGC-1
α
(pe oxisome p oli e a o -ac i a ed ecep o gamma coac i a o 1-
α
) is an impo an egula o o
he ansc ip ion o nuclea -encoded genes implica ed in mi ochond ial biogenesis [
97
]. Th ough i s
ole as a ansc ip ional coac i a o , PGC-1
α
also egula es bo h OXPHOS and ROS de oxi ying
enzymes [
101
]. Thus, in b eas cance , highe PGC-1
α
exp ession is co ela ed wi h a poo
p ognosis [
102
]. The use o XCT790, a compound ha educes colony o ma ion in so aga by
egula ing PGC-1
α
, showed a educ ion in CSCs [
73
]. Addi ionally, panc ea ic CSCs exhibi ed high
le els o PGC-1
α
, making hese cells mo e sensi i e o me o min [
18
]. The MAPK/ERK pa hway is
also implied in mi ochond ial biogenesis due o i s ole in bo h in insic and acqui ed esis ance o
MAPK inhibi o s (MAPKi). MAPKi ea men showed he p esence o a esis an popula ion, wi h
high mi ochond ial biogenesis and an ac i e OXPHOS me abolism [63].
All hese esul s show ha mi ochond ial popula ion should be inely uned in no mal cells o
a oid an imbalance, ei he due o excessi e biogenesis o due o de ec s (mu a ions o dele ions) in
m DNA, which will p obably cause changes in me abolism.
4. Mi ochond ial Me abolism in CSC Resis ance
Impo an ly, each CSC subpopula ion inside a umo may exhibi a di e en me abolic p o ile o
o he CSCs o he umo mass, wi h his he e ogenei y associa ed wi h esis ance o ea men . Thus,
con adic o y esul s ha e been ob ained ega ding he me abolic p o ile o CSCs. In some cases, hey
ha e been desc ibed as mainly glycoly ic [
61
,
103
–
106
]; o he a icles ha e indica ed ha CSCs a e
p ima ily dependen on OXPHOS [18,61,76,107].
The me abolic s a us o CSCs is e y impo an in d ug esis ance mechanisms because, when
glycoly ic CSCs di e en ia e and p oli e a e, a change om anae obic o ae obic me abolism can be
obse ed [14]. Howe e , CSCs om di e en umo ypes ha e also been desc ibed as depending on
OXPHOS o mos o hei ene gy. The inc eased e iciency o OXPHOS-based me abolism would, in
heo y, allow cance cells o use he nu ien s be e , allowing hem o su i e in nu i ionally poo
en i onmen s [
35
]. S udies ha e sugges ed ha ea men - esis an CSCs a e less glycoly ic, indica ing
ha speci ic OXPHOS inhibi ion could a ack hese cells, helping hem o escape om damage in
hypoxic a eas o he umo . Thus, cells unde se e e hypoxia become mo e esis an o i adia ion han
cells in no moxia [108].
A he molecula le el, he ypical me abolic lexibili y o cance is based on he econnec ion
among he di e en me abolic pa hways, achie ed h ough he syn hesis o deg ada ion o key p o eins
ha allow me aboli es o change pa hways acco ding o cells’ needs. The i s o he desc ibed
mechanisms o his me abolic emodeling is he so-called Wa bu g e ec , in which cells use la ge
amoun s o glucose in he p esence o oxygen [
109
]. This leads o he o ma ion and sec e ion o
lac a e in a mechanism called ae obic glycolysis [
86
,
109
]. Al hough his mechanism is ine icien in
ene gy p oduc ion in he o m o ATP, glucose abso p ion om umo cells is usually highe , leading o
a ne ATP p oduc ion simila o he le el achie ed wi h OXPHOS, caused by di e en mu a ions in
espi a o y complexes [48].
The low ROS le els p esen in CSCs could be due o e en s leading o me abolic ep og amming,
which is essen ial o main aining sel - enewal and imp o ing he an ioxidan de ense mechanism [
14
].
Thus, glycoly ic CSCs a e usually adap ed o he ypical hypoxic en i onmen o many umo s, in
Cells 2020,9, 1693 7 o 28
which he glycoly ic me abolism p e ails o coun e ac a low mi ochond ial le el. Speci ic physiological
me aboli es, such as py u a e, e ahyd o ola e, and glu amine, can unc ion as cy o oxic agen s in
CSCs when adminis e ed a doses ha dis up he edox NADP
+
/NADPH a io [
110
]. Thus, py u a e
accumula ion mimics he blockade o he espi a o y chain pe o med by he binding o an imycin A
o cy och ome c educ ase in mi ochond ial complex III [110,111].
High ALDH1 (aldehyde dehyd ogenase-1) exp ession le els a e cha ac e is ic o CSCs, which
a e ela ed o inc eased esis ance o chemo he apeu ic agen s in sa coma, b eas and lung
CSCs [
112
–
114
]. High ALDH exp ession p o ec s agains he oxic e ec s o RNOS p oduc ion
de i ed om chemo he apeu ic ea men , so ha i s inhibi ion u he aises he RNOS le els,
igge ing apop osis [
115
]. High ALDH ac i i y is associa ed wi h high le els in he mi ochond ial
mass, bo h in cell lines and samples de i ed om pa ien s, sugges ing highe mi ochond ial biogenesis
o e a ded deg ada ion o mi ochond ia. Thus, he mi ochond ial biogenesis inhibi o doxycycline
a ge s ALDH
+
b eas CSCs [
116
]. These esul s could be ela ed o highe exp ession o mi ochond ial
ALDH iso o ms [117].
The egula ion among he enzymes o he glycoly ic pa hway, OXPHOS and TCA cycle, all
in ol ed in he syn hesis o ATP and main enance o he NAD
+
/NADH a io, esul s in high me abolic
plas ici y in a la ge p opo ion o CSCs. The mi ochond ia ake small molecules, such as py u a e, a y
acids and amino acids, om ca abolic eac ions o ob ain educed powe in he o m o NADH and/o
FADH
2
. These molecules allow, h ough hei oxida ion, he elec on ans e in he mi ochond ial
espi a o y chain om wa e o molecula oxygen.
Impo an ly, design s a egies ha a ge a ype o me abolism can lead o umo cells, especially
CSCs, wi h highe me abolic plas ici y, changing hei me abolism o adap o he new si ua ion. Thus,
conside ing combined ea men is impo an o sho -ci cui mi ochond ial me abolic plas ici y.
4.1. Role o he Mi ochond ial Respi a o y Chain in CSC Resis ance
The mi ochond ial espi a o y chain, o elec on anspo chain (ETC), comp ises ou enzyma ic
complexes, among which complex II is comple ely encoded in he nuclea genome, while complexes
I, III and IV a e s ill encoded in m DNA [
86
]. The highe mu a ion a e o m DNA han nuclea
DNA allows he appea ance o ce ain mu a ions ha can a ec he assembly o he mi ochond ial
complexes bu allowing i s pa ial unc ioning. Thus, due o he he e oplasmy exis ing in cells [
86
],
mu a ions in m ND1 allow he unc ioning o Complex I bu , when he mu a ed popula ion eached
a h eshold, hey beha e as umo supp esso s, p e en ing he assembly o complex I and also educing
i s me as a ic abili y [
118
]. Thus, m DNA mu a ions comp ising bo h he ac i i y and assembly o
OXPHOS complexes may dec ease o e en inhibi umo g ow h in xenog a models [
118
]. Howe e ,
a pa ial ETC inhibi ion caused by mu a ions in m DNA, ha mimics he e ec o m DNA deple ion,
p omo ed a mig a o y pheno ype in cul u ed cells, beha ing as oncogenic mu a ions [
119
]. In his way,
ce ain mu a ions beha e as oncogenic when appea ing a low le els in he m DNA popula ion bu
became umo supp esso s in homoplasmy.
Due o he ole o he ou complexes in ol ed in OXPHOS in elec on lux, inhibi ing a speci ic
complex is simila o ha ob ained by inhibi ing o he s (Figu e 2A). D ugs inhibi ing mi ochond ial
espi a ion include me o min, a complex I inhibi o ha educes umo igenesis [
120
]. In non-CSCs
om panc ea ic cance cells, me o min induced cell cycle a es , while apop osis was induced in
CSCs [
18
,
107
]. This molecule can e e se he esis ance o chemo he apy d ugs in b eas cance
cells [
121
]. In ac , me o min ea men speci ically elimina es CD44
+
/CD24
−
CSCs, showing posi i e
syne gy wi h doxo ubicin and esul ing in delayed umo ecu ence [
122
]. Addi ionally, me o min,
also desc ibed as a PI3K/Ak /mTOR signaling inhibi o , educed CSC esis ance o emozolomide,
a chemo he apy d ug ha causes DNA damage [
123
]. Howe e , me o min esis ance has also
been de ec ed in ce ain umo s
in i o
[
18
], making i necessa y o use combined ea men s o
mo e powe ul de i a i es. Thus, he combina ion o me o min wi h 2-deoxy-D-glucose (2-DG),
a glycolysis inhibi o , inc eased he cell dea h pe cen age and educed umo g ow h in xenog a
Cells 2020,9, 1693 8 o 28
models [
124
]. The use o phen o min, a biguanide de i a i e simila o me o min and a complex I
inhibi o , bu wi h highe an ineoplas ic e iciency, can be used alone o combined wi h o he d ugs
agains CSCs [
125
]. Combined ea men o phen o min wi h gossypol, an inhibi o o ALDH and
a ious an i-apop o ic componen s o he BCL-2 amily, supp esses s emness and p oduces a signi ican
educ ion in in asion capaci y and cell iabili y [
126
]. Ano he d ug, menadione, exe s a double e ec
h ough complex I inhibi ion and he induc ion o ROS, and p e en s he appea ance o esis ance [
127
].
Pi inium pamoa e, a complex II inhibi o , educes umo sphe e o ma ion in di e en cance cell
lines [
75
]. Simila ly, an imycin A and a o aquone, bo h complex III inhibi o s, signi ican ly educe
CSCs [
78
,
128
]. A o aquone a ge CSCs p e e en ially, p oducing an inc eased glycoly ic a e, wi h
no e ec on no mal ib oblas s [
78
]. ATP syn hase, also called Complex V, can be inhibi ed by
oligomycin, bu i s high oxici y p e en s i s use as a chemo he apeu ic d ug [
76
]. Howe e , i could
be used a lowe concen a ions combined wi h o he d ugs, such as 2-DG o niclosamide, educing
he CSC pe cen age in glioblas oma and o a ian and b eas cance cells [129–131]. Ano he Complex
V inhibi o , bedaquiline, is a d ug app o ed o mul id ug- esis an ube culosis [
132
] ha a ge s
CSCs p e e en ially [
133
]. O he d ugs, such as es e a ol, can co ec de ec s in complexes I and IV,
dec easing he g ow h a e and in asi e po en ial o di e en cance cell lines [
77
,
134
]. This d ug has
been desc ibed o induce mi ochond ial dys unc ion, cy och ome c elease and caspase ac i a ion in
panc ea ic cance [
135
]. In o he cases, OXPHOS mus be inhibi ed o bypass acqui ed esis ance o
ce ain d ugs. Thus, OXPHOS p omo es esis ance o cy a abine, an an ime aboli e, in animal AML
models, and combined ea men wi h OXPHOS inhibi o s es o es sensi i i y [136].
OXPHOS can also be inhibi ed by changes in he mi ochond ial memb ane po en ial. Salinomycin
is a K
+
ionopho e ha , ac ing as an OXPHOS inhibi o , seems o educe he CSC pe cen age bo h
in i o
and
in i o
in di e en ypes o cance [
137
–
139
]. Salinomycin can kill cells esis an o di e en
chemo he apeu ic d ugs, such as doxo ubicin, cispla in, gemci abine, emozolomide, e apamil o
ima inib and sensi izes adio esis an cells [
139
]. The oxici y o salinomycin is ampli ied unde low
oxygen and/o glucose le els, inc easing RNOS le els [
140
]. In his si ua ion, AMP-ac i a ed p o ein
kinase (AMPK) is ac i a ed, igge ing au ophagy and allowing his d ug o ac as an an i-CSC molecule.
Thus, he combina ion o AMPK agonis s, such as me o min and 2-DG, wi h salinomycin could be
used o o e come CSC esis ance [
139
]. Salinomycin also causes mi ochond ial hype pola iza ion,
inducing mi ophagy o dys unc ional mi ochond ia [
141
]. Salinomycin can a ge and kill cance
cells p e e en ially, bu no p ima y cells [
141
]. A simila e ec , he p e e ence o cance cells, has
been ound o ano he OXPHOS inhibi o , VLX600, inc easing he e ec o i ino ecan in xenog a
models [
142
]. This compound also induces AMPK phospho yla ion in umo cell lines [
142
] and
sensi izes cells o glucose s a a ion [143].
In mos o hese cases, OXPHOS inhibi ion causes mi ochond ial imbalance, causing inc eased
RNOS le els and/o me abolic swi ch o glycolysis. In solid umo s, due o he poo blood supply,
bo h he oxygen and glucose low le els will comp omise me abolic ewi ing om OXPHOS o
glycolysis i mi ochond ial OXPHOS is inhibi ed. Thus, as a consequence o OXPHOS imbalance,
oxida i e s ess due o RNOS accumula ion can p omo e he igge ing o apop osis in CSCs based on
OXPHOS me abolism.
Cells 2020,9, 1693 9 o 28
Figu e 2.
Mi ochond ial me abolism a ge ing can o e come CSC esis ance. (
A
) Mi ochond ial el on
anspo chain (ETC), co e o oxida i e me abolism, showing some o he desc ibed inhibi o s o
each complex (blue lines) used o CSC ea men . CI: complex I; CII: complex II; CIII: Complex
III, CIV: Complex IV; CV: Complex V; Q: ubiquinone; Cc: cy och ome c. Ou e mi ochond ial
memb ane appea s in ed, while inne mi ochond ial memb ane is colo ed in g ey. Salinomycin
causes mi ochond ial memb ane po en ial (
∆Ψ
m) dis up ion. (
B
) Reac i e oxygen species p oduced as
a consequence o ETC. Inhibi o s o mi ochond ial de oxi ying enzymes a e labelled wi h a blue line.
Red a ow indica es a RNOS enhance . ATO: A senic ioxide; GSH: glu a hione; GSSG: glu a hione
disul ide; GR: glu a hione educ ase; GPX: glu ha hione pe oxidase. (
C
) Glycoly ic me abolism,
showing inhibi o s o GLUT1 and hexokinase, blocking glycolysis a i s beginning, and dichlo oace a e
(DCA), ha inhibi s py u a e dehyd ogenase kinase (PDK) and allow he inco po a ion o py u a e
in o he ica boxylic acid (TCA) cycle. Blue lines co espond o glycoly ic inhibi o s, while ed
a ows belong o HIF-1
α
, a glycoly ic enhance . 2-DG: 2-deoxyglucose; GPI: glucose-6-phospha e
isome ase; G3PDH: glyce aldehyde-3-phospha e dehyd ogenase; PGK1: phosphoglyce a e kinase;
PGM: phosphoglyce a e mu ase. (
D
) Summa y o a y acid oxida ion (FAO) me abolism. E omoxi
and pe hexiline, inhibi o s o CPT1 (blue line) diminished CSC popula ion, by educing mi ochond ial
inco po a ion o a y acids. (
E
) Pa hways ela ed o he TCA cycle equen ly modi ied in CSCs. Blue
a ows co espond o aconi ase (ACO) knockdown. SDH: succina e dehyd ogenase; FH: uma a e
hyd a ase; IDH: isoci a e dehyd ogenase; mIDH: mu a ed IDH. GLS: glu aminase; GDH: glu ama e
dehyd ogenase; IDH: isoci a e dehyd ogenase; ACLY: ATP ci a e lyase.
Cells 2020,9, 1693 16 o 28
induce apop osis in pacli axel- esis an cells [
167
]. BCL-2 inhibi ion also impai s OXPHOS, educing
he su i al o OXPHOS-dependen CSCs in AML [238].
Due o apop osis-acqui ed esis ance o CSCs, he use o inhibi o s o BCL2 amily would educe
he CSC popula ion.
Figu e 4.
Summa y o in insic apop o ic pa hway. BCL-2, as an iapop o ic p o ein, inhibi s
he o ma ion o po es by BAX/BAK ha allow cy och ome c elease o he cy oplasm, whe e i
in e ac s wi h Apa -1 o cons i u e apop osome, allowing caspase cascade. D ugs a ge ing apop osis
comp ise dissipa e s o mi ochond ial memb ane po en ial (
∆Ψ
m) o BCL-2 inhibi o s (blue lines) o
molecules enhancing o ma ion o BAX/BAK po es ( ed a ow).
8. Conclusions
Mi ochond ia beha e as an o ganelle o ex ao dina y me abolic plas ici y, capable o modi ying
hei di e en pa hways o suppo (cance ) cell su i al. Addi ionally, he combina ion o di e en
chemo he apeu ic agen s o adia ion is a good s a egy o o e come he esis ance o CSCs. Thus,
blocking a leas wo me abolic pa hways simul aneously would educe he possibili y o a elapse, as
well as he possible de elopmen o esis ance. Howe e , and due o me abolic plas ici y, i would
be impo an o know which pa hway(s) is p e alen in a speci ic CSC popula ion, in o de o use
d ugs ha could a ge hem, inc easing i s e ec i eness. Addi ionally, i would be in e es ing o
s udy he design o syne gis ic ea men s ocused on CSCs mi ochond ial me abolism, o educe
elapse p obabili y.
Funding:
This esea ch was unded by g an s om he Minis e io de Ciencia, Inno aci
ó
n y Uni e sidades (MCIU)
Plan Es a al de I+D+I 2018, a la Agencia Es a al de In es igaci
ó
n (AEI) y al Fondo Eu opeo de Desa ollo Regional
(MCIU/AEI/FEDER, UE): RTI2018-097455-B-I00; g an om AEI-MICIU/FEDER (RED2018-102723-T); om CIBER
de C
á
nce (CB16/12/00275), co- unded by FEDER om Regional De elopmen Eu opean Funds (Eu opean Union);
om Conseje
í
a de Salud (PI-0397-2017) and Conseje
í
a o Econom
í
a, Conocimien o, Emp esas y Uni e sidad
o he Jun a de Andaluc
í
a (P18-RT-2501). Also especial hanks o he Fundaci
ó
n AECC and Fundaci
ó
n Eugenio
Rod iguez Pascual o suppo ing his wo k.

Cells 2020,9, 1693 17 o 28
Con lic s o In e es :
The au ho s decla e no con lic o in e es . The unde s had no ole in he design o he s udy;
in he collec ion, analyses, o in e p e a ion o da a; in he w i ing o he manusc ip , o in he decision o publish
he esul s.
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