Role of Mitochondria in Cancer Stem Cell Resistance

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   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. Re e ences 1. Den on, A.E.; Robe s, E.W.; Fea on, D.T. 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