Neu obiology o Disease 184 (2023) 106199
A ailable online 14 June 2023
0969-9961/© 2023 Published by Else ie Inc. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
B igh ness and shadows o mi ochond ial ROS in he b ain
Daniel Jimenez-Blasco
a
,
b
,
c
,
*
, Angeles Almeida
a
,
b
,
*
, Juan P. Bola˜
nos
a
,
b
,
c
,
*
a
Ins i u o de Biología Funcional y Gen´
omica (IBFG), Uni e sidad de Salamanca, CSIC, Salamanca, Spain
b
Ins i u o de In es igaci´
on Biom´
edica de Salamanca (IBSAL), Hospi al Uni e si a io de Salamanca, Uni e sidad de Salamanca, CSIC, Salamanca, Spain
c
Cen o de In es igaci´
on Biom´
edica en Red de F agilidad y En ejecimien o Saludable (CIBERFES), Mad id, Spain
ARTICLE INFO
Keywo ds:
As ocy es
Reac i e oxygen species
Mi ochond ia
Supe complexes
Neu ons
Glu a hione
ABSTRACT
Mi ochond ial eac i e oxygen species (mROS) ha e been gene ally conside ed ha m ul byp oduc s wan ed o
clea when ele a ed o a oid b ain damage. Howe e , he abundance o mROS in as ocy es is e y high -abou
one o de o magni ude abo e ha in neu ons-, despi e hey a e essen ial o p ese e cell me abolism and animal
beha io . He e, we ha e ocused on his appa en ambigui y by discussing (i) he in insic mechanisms ac-
coun ing o he highe p oduc ion o mROS by he mi ochond ial espi a o y chain in as ocy es han in neu ons,
(ii) he speci ic molecula a ge s o as ocy ic bene icial mROS, and (iii) how dec eased as ocy ic mROS causes
excess neu onal mROS leading o cellula and o ganismal damage. We hope ha his mini- e iew se es o
cla i ying he appa en con o e sy on he bene icial e sus dele e ious aces o ROS in he b ain om molecula
o highe -o de o ganismal le els.
1. P oduc ion o mi ochond ial ROS by as ocy es
Mi ochond ia a e conside ed he main p oduce s o ROS wi hin he
cell (Mu phy, 2009). Amongs he ple ho a o ROS sou ces wi hin he
mi ochond ia (B and, 2010), i appea s ha a la ge pool comes om he
mi ochond ial espi a o y chain (MRC) du ing oxida i e phospho yla-
ion (OXPHOS) (Mu phy, 2009). Thus, MRC complexes couple he
oxida ion o educed co ac o s (NADH o FADH
2
) wi h p o on pumping
o he mi ochond ial in e memb ane space, gene a ing he elec o-
chemical g adien used by ATP syn hase o gene a e ATP (En iquez,
2016). To egula e he e iciency o his sys em, MRC complexes I, III
and IV can be o ganized and assembled in o highe -o de s uc u es
called supe complexes (SCs) (Chaban e al., 2014; En iquez, 2016).
No ably, he supe -assembly o complexes I and III -a di e en s oi-
chiome ies- inc eases elec on lux in o he MRC likely enhancing i s
e iciency (Lapuen e-B un e al., 2013). Con e sely, disassembly o
complex I om III leading o a highe p opo ion o ee complex I esul s
in lowe MRC e iciency (Lapuen e-B un e al., 2013). The MRC may
hus adop a ange o s uc u al con o ma ions wi hin a cell o issue o
adap agains speci ic me abolic ci cums ances (Gua as e al., 2016). Fo
ins ance, wi hin he b ain, neu ons show a cons i u i e p e e ence o
supe -assemble complex I and III; in con as , as ocy es display a highe
p opo ion o disassembled complex I (Lopez-Fabuel e al., 2016).
The e o e, his di e en MRC con o ma ion is likely a e lec ion o
dis inc me abolic si ua ions in neu ons and as ocy es, mo e OXPHOS
dependen in he o me (Ala ian e al., 2011; Ku e e al., 2019;
Almeida e al., 2001; Almeida e al., 2004; Bola˜
nos e al., 1995; He -
e o-Mendez e al., 2009).
In mammals, complex I consis s o 45 subuni s wi h a o al molecula
weigh o ~980 KDa (Ca oll e al., 2003; Ca oll e al., 2006). All hese
subuni s a e assembled o o m h ee unc ional modules, namely he N
module, which is placed in he pe iphe al a m o he complex and ac-
cep s elec ons om NADH, he Q module, which eleases elec ons o
ubiquinone, and he P module, placed in he memb ane-embedded a m,
whe e i is esponsible o he ansloca ion o p o ons in o he in e -
memb ane space (Ca oll e al., 2003; Ca oll e al., 2006; Ma hiesen and
Hage hall, 2002; Mimaki e al., 2012). No ably, complex I can d i e
elec ons no only o ubiquinone, bu also o O
2
, o ming supe oxide
anion (O
2
•-
, he o iginal ROS), a unc ion ha is known o ake place a
he N-module. Using di e en p opo ions o MRC complexes in
Abb e ia ions: CB
1
, cannabinoid-1 ecep o ; Cys-Gly, cys einyl-glycine; G6PD, glucose 6-phospha e dehyd ogenase; HDAC4, his one deace ylase-4; HIF1
α
, hyp-
oxia-inducible ac o -1
α
; m CB1, mi ochond ial cannabinoid-1 ecep o ; mROS, mi ochond ial eac i e oxygen species; MRC, mi ochond ial espi a o y chain;
NDUFS4, NADH:ubiquinone oxido educ ase subuni S4; NRF2, nuclea e y h oid- ela ed ac o 2; 3NP, 3-ni op opionic acid; OXPHOS, mi ochond ial oxida i e
phospho yla ion sys em; PPP, pen ose-phospha e pa hway; ROS, eac i e oxygen species; SCs, supe complexes; THC, Δ
9
- e ahyd ocannabinol..
* Co esponding au ho s a : Ins i u o de Biología Funcional y Gen´
omica (IBFG), Uni e sidad de Salamanca, CSIC, Salamanca, Spain.
E-mail add esses: [email p o ec ed] (D. Jimenez-Blasco), [email p o ec ed] (A. Almeida), [email p o ec ed] (J.P. Bola˜
nos).
Con en s lis s a ailable a ScienceDi ec
Neu obiology o Disease
jou nal homepage: www.else ie .com/loca e/ynbdi
h ps://doi.o g/10.1016/j.nbd.2023.106199
Recei ed 12 Feb ua y 2023; Recei ed in e ised o m 10 June 2023; Accep ed 12 June 2023
Neu obiology o Disease 184 (2023) 106199
2
liposomes, i was ound ha SCs o ma ion dec eased ROS p oduc ion by
complex I (Ma anzana e al., 2013). This obse a ion was in e p e ed o
be consequence o he lowe p obabili y o elec ons o be ans e ed
om NADH o O
2
( o ming O
2
•-
) by complex I, gi en he e icien lux o
elec ons om NADH o ubiquinone in supe -assembled MRC (Ma -
anzana e al., 2013). In good ag eemen wi h his hypo hesis, as ocy es
-which show a highe p opo ion o disassembled complex I han neu-
ons-, na u ally p oduce mo e ROS han neu ons (Lopez-Fabuel e al.,
2016). I should be no ed ha his pa allelism is no a simple co ela ion,
because he le els o ROS abundances in bo h cell ypes we e e e sed by
gene ically al e ing he abili y o complex I o assemble wi h complex III
(Lopez-Fabuel e al., 2016). Thus, he assembly o complex I wi h
complex III de e mines complex I-media ed ROS p oduc ion, which in
as ocy es occu s a one o de o magni ude abo e ha in neu ons
(Fig. 1).
2. Molecula a ge s o as ocy ic mi ochond ial ROS
A key ques ion ega ding he in iguing high mROS o ma ion in
as ocy es would be unde s anding hei impac on cellula and animal
wel a e. Add essing his ques ion implies he implemen a ion o a sys-
em ha is able o swi ch o mROS abundance in as ocy es in i o o
assess i s consequences. This was achie ed by gene ically enginee ing an
inducible mouse model ha exp esses he an ioxidan enzyme ca alase
in he mi ochond ial ma ix o as ocy es in adul hood (Vicen e-
Gu ie ez e al., 2019). E icien a enua ion o mROS in as ocy es dis-
played a p o ound al e a ion in he ansc ip ional inge p in o as o-
cy es and in he b ain me abolomics signa u e. Essen ially, i was ound
inc eased he ibose-5-phospha e/6-phosphoglucona e a io and
dec eased he py u a e/glucose a io, indica ing inc eased pen ose-
phospha e pa hway (PPP) and dec eased glycolysis, a me abolic
swi ch ha was con i med by lux analysis (Vicen e-Gu ie ez e al.,
2019). In e es ingly, exp ession o glucose-6-phospha e dehyd ogenase
(G6PD), he i s and a e-limi ing s ep o he PPP, was inc eased in he
mROS-ab oga ed as ocy es (Vicen e-Gu ie ez e al., 2019), indica ing
ha his enzyme migh be a di ec o indi ec mROS a ge . G6PD is
known o be ansc ip ionally ep essed by he mic o-RNA 206 (miR-
206) (Coda e al., 2015), he exp ession o which is in u n ep essed by
he nuclea abundance o he edox senso ansc ip ional modula o ,
his one deace ylase-4 (HDAC4) (Winbanks e al., 2011). No ably, miR-
206 le els in mROS-a enua ed as ocy es we e dec eased (Vicen e-
Gu ie ez e al., 2019), an e ec ha was escued by o e -exp ession o
miR-206 (Vicen e-Gu ie ez e al., 2019). Mo eo e , nuclea abundance
o HDAC4 was highe in mROS-dec eased as ocy es, indica ing ha he
educed (ac i e) o m o HDAC4 was p edominan in hese cells. Finally,
inhibi ing HDAC ac i i y wi h ichos a in A p e en ed he inc ease in
G6PD in mROS-a enua ed as ocy es. Taken oge he , hese obse a-
ions sugges ha a physiological signaling ole o mROS in as ocy es
would be o keep HDAC4 oxidized and seques e ed in he cy osol o
allow miR-206 exp ession, which des abilizes G6PD and dec eases PPP
ac i i y, in u n sus aining glycolysis (Vicen e-Gu ie ez e al., 2019)
(Fig. 1).
Amongs o he unc ions, PPP main ains he NADPH(H
+
)/NADP
+
a io, which was ound o be dec eased in mROS-impo e ished as o-
cy es, sugges ing inc eased NADPH(H
+
) consump ion (Vicen e-Gu ie -
ez e al., 2019). NADPH(H
+
) oxidases (NOXs), which p oduce
supe oxide anion (O
2
•-
), a e highly ac i e NADPH(H
+
) consuming en-
zymes (Naye nia e al., 2014). NOX-1 and -2 we e ound inc eased in he
ansc ip omic analysis o he mROS-lowe ed as ocy es (Vicen e-
Gu ie ez e al., 2019). In e es ingly, hese NOX-1 and -2 a e localized in
he plasma memb ane wi h hei ac i e si e acing o he ex acellula
space. Indeed, as ocy es dep i ed o mROS show enhanced ex acel-
lula O
2
•-
(Vicen e-Gu ie ez e al., 2019). Hence, as ocy ic mROS
physiologically down egula e NOXs exp ession and keeps ex acellula
O
2
•-
p oduc ion low. Howe e , how mROS downmodula es NOXs
exp ession? I should be men ioned ha NOX-1 and -2 exp ession a e
down egula ed by he nuclea ac o -e y h oid 2- ela ed ac o -2 (NRF2)
(Ko ac e al., 2015; Pendyala and Na a ajan, 2010), a ansc ip ion
ac o known o be ac i a ed by ROS o go e n he exp ession o a wide
ba e y o an ioxidan genes aimed o p o ec agains cellula edox
s ess (Hayes and McMahon, 2009; Tebay e al., 2015). NRF2 is
ep essed by Kelch-like ECH-associa ed p o ein 1 (KEAP1)-Cullin 3
Fig. 1. Physiological e sus pa hological oles o mi ochond ial ROS (mROS) in as ocy es and neu ons. Le . Unde physiological condi ions, mROS gene a ion by he
mi ochond ial espi a o y chain o as ocy es is high, in pa due o he disassembly o complex I (I) om complex III (III). Howe e , in neu ons, complex I is mo e
assembled wi h complex III esul ing in lowe mROS gene a ion. High as ocy ic mROS sus ains ac i e ansc ip ion ac o s HIF1 (hypoxia-inducible ac o -1), which
con ibu e o p ese e glycolysis and NRF2 (nuclea ac o -e y h oid 2- ela ed ac o -2), which p omo es he exp ession o γ-glu amyl-cys eine syn he ase (γ-GCS)
and hence glu a hione (GSH) biosyn hesis; no ably, by ep essing he exp ession o NADH oxidases-1 and -2 (NOX-1, −2), as ocy ic mROS down egula es ex a-
cellula O
2
•-
. Glycoly ically- eleased lac a e and GSH-de i ed Cys-Gly can be aken up by neu ons, whe e hey a e used o uel OXPHOS (oxida i e phospho yla ion)
and p ese e he an ioxidan s a us, espec i ely, main aining o ganismal wel a e. Righ . Complex I des abiliza ion in as ocy es lead o mROS educ ion. Ei he by
his mechanism o by selec i e sca enging o mROS in as ocy es, he educ ion o as ocy ic mROS leads o he e e sal o HIF1 and NRF2 ansc ip ional ac i i y,
causing educed lac a e and Cys-Gly elease, and inc eased O
2
•-
. In addi ion, complex I disassembly om complex III in neu ons, which has been obse ed in Pa -
kinson’s disease, in insically may con ibu e o pa hological high neu onal mROS and OXPHOS ine iciency. Al oge he , hese ac o s con ibu e o neu onal ene gy
ailu e and edox s ess, causing o ganismal damage.
D. Jimenez-Blasco e al.
Neu obiology o Disease 184 (2023) 106199
3
(CUL3)-RING-box p o ein 1 (Rbx1), an E3 ubiqui in ligase ha a ge s
NRF2 o p o easomal deg ada ion (Tebay e al., 2015). In e es ingly,
he p o ein exp ession o CUL3 and KEAP1 a e e y low in as ocy es
when compa ed wi h neu ons (Bell e al., 2015; Jimenez-Blasco e al.,
2015), which explains he cons i u i ely highe ac i i y o NRF2 in as-
ocy es (Bax e e al., 2015; Jimenez-Blasco e al., 2015). Mo eo e ,
ROS oxidizes KEAP1 o inac i e i , p omo ing NRF2 ansc ip ional ac-
i i y (Tebay e al., 2015). The e o e, i is emp ing o specula e ha he
na u ally high mROS abundance in as ocy es con ibu e o p ese e
NRF2 ansc ip ional ac i i y, hence explaining he inc eased NOX-1
and -2 exp ession in he mROS-a enua ed as ocy es (Vicen e-Gu ie -
ez e al., 2019). Indeed, exp essing a cons i u i ely ac i e NRF2 iso o m
in mROS-impo e ished as ocy es was su icien o escue he inc eased
NOX-1 and -2 mRNA abundances and he enhanced ex acellula O
2
•-
elease. Al oge he , hese obse a ions s ongly sugges ha mROS in
as ocy es physiologically downmodula e he elease o po en ially
damaging O
2
•-
in o he ex acellula space (Fig. 1).
3. Neu opa hological consequences o dec eased as ocy ic
mROS
In good ag eemen wi h he obse a ions ha mROS p oduc ion by
as ocy es igge s he ac i a ion o molecula mechanisms aimed o
p ese e he me abolic and edox s a us o hese cells, loss o mROS
causes b ain damage. In essence, dis up ion o physiological mROS in
as ocy es weakens he signaling pa hways ha sus ain NRF2-
an ioxidan sys em and glycolysis (Jimenez-Blasco e al., 2020; Vice-
n e-Gu ie ez e al., 2019). In consequence, neighbo neu ons become
dys unc ional e en ually leading o damage and highe -o de
al e a ions.
By ab oga ing as ocy ic mROS using he mi ochond ial-speci ic
exp ession o ca alase, NRF2-media ed an ioxidan sys em is down-
egula ed esul ing in he impai men o glu a hione (GSH) biosyn hesis
(Vicen e-Gu ie ez e al., 2019). GSH, which is e y abundan in as o-
cy es (Bola˜
nos e al., 1996; Maka e al., 1994), is clea ed in hese cells
in o he dipep ide cys einyl-glycine (Cys-Gly) by he ac ion o he
ec oenzyme γ-glu amyl- anspep idase o elease he dipep ide in o he
ex acellula space (Saga a e al., 1993). Cys-Gly can hen be aken up by
neu ons, which, being unable o ake up cys eine (Saga a e al., 1993),
use he dipep ide and glu ama e o syn hesize GSH (D ingen e al., 1999)
and hence o sus ain neu onal an ioxidan p o ec ion (D ingen e al.,
1999; Jimenez-Blasco e al., 2015). Acco dingly, when as ocy ic mROS
a e ab oga ed, he NRF2-media ed GSH shu ling om as ocy es o
neu ons is impai ed, esul ing in neu onal GSH loss, edox s ess,
cellula damage and cogni i e impai men in mice (Vicen e-Gu ie ez
e al., 2019). F om hese obse a ions, i could be concluded ha , unde
a physiological poin o iew, as ocy es p ese e a na u ally occu ing
high mROS o ma ion aimed o sus ain he an ioxidan machine y,
whe eas neu ons a e weak mROS p oduce s, hence equi ing he
con inuous supply o an ioxidan s om neighbo as ocy es. This is
suppo ed by indings ob ained using he mi ochond ial- agged ca alase
gene ic exp ession in as ocy es o in neu ons in i o upon a edox s ess
s imulus. Thus, p e en ing he inc ease in mROS in as ocy es does no
a oid he mo o discoo dina ion caused by he in ape i oneal injec ion
o he neu o oxin 3-ni op opionic acid (3NP); howe e , p e en ing he
inc ease in mROS in neu ons ully a oids 3NP-media ed mo o dis-
coo dina ion (Vicen e-Gu ie ez e al., 2021). Hence, high mROS in as-
ocy es is physiological, so i s loss causes neu opa hology; in con as ,
low mROS in neu ons is physiological, so i s inc ease causes damage
(Fig. 1). O no e, complex I disassembly om complex III has been
obse ed in Pa kinson’s disease pa ien s and in neu ons om a mouse
model o his diso de (Lopez-Fabuel e al., 2017) indica ing ha he
co ec MRC assembly in neu ons impac s on OXPHOS e iciency and
damaging mROS o ma ion.
Ano he piece o e idence ha con i ms he physiological impo -
ance o high o ma ion o mROS by as ocy es is shown upon ch onic
adminis a ion o cannabinoids. Thus, pe sis en cannabis consump ion
is well known o cause loss o social in e ac ion, amongs o he psy-
choses (Busque s-Ga cia e al., 2022). Howe e , he molecula mecha-
nism ha igge s his e ec has long been elusi e. The key obse a ion
ha cannabinoid ecep o -1 (CB1) a e exp essed in mi ochond ia
(m CB1), whe e hei ac i a ion causes inhibi ion o mi ochond ial
complex I (Bena d e al., 2012), led o ollowing s udy showing ha , by
inhibi ing complex I, adminis a ion o cannabinoid agonis s, such as
Δ
9
- e ahyd ocannabinol (THC), igge ed cogni i e impai men in mice
(Hebe -Cha elain e al., 2016). In e es ingly, m CB1 ecep o s a e also
p esen in as ocy es (Gu ie ez-Rod iguez e al., 2018), he ac i a ion o
which also leads o complex I inhibi ion (Jimenez-Blasco e al., 2020).
The mechanism causing complex I inhibi ion was un eiled using na i e
elec opho esis o he MRC complexes and supe complexes (Jimenez-
Blasco e al., 2020). In essence, i was ound ha pe sis en m CB1
ac i a ion in as ocy es causes loss o he N module o complex I.
Mechanis ically, m CB1 ecep o s, by inhibi ing p o ein kinase A, causes
dephospho yla ion o many p o eins, including he complex I N-module
subuni , NDUFS4 (NADH:ubiquinone oxido educ ase subuni S4)
(Jimenez-Blasco e al., 2020). In ac , p o ein kinase A was p e iously
known o phospho yla e NDUFS4 subuni a i s Se
173
posi ion as an
essen ial s ep in he assembly o he N-module (De Rasmo e al., 2008).
Consequen ly, ch onic ac i a ion o m CB1 in as ocy es no only in-
hibi s he abili y o complex I o educe ubiquinone -hence inhibi ing he
ene gy conse ing ole o complex I -, bu i also abla es i s abili y o
physiologically gene a e ROS (Jimenez-Blasco e al., 2020). This leads o
dec eased mROS gene a ion ha esul s in loss o ac i a ion o hypoxia-
inducible ac o -1
α
(HIF1
α
), known o be s abilized by ROS o p omo e
he ansc ip ional ac i i y o HIF1 (Pa en e al., 2010). Since HIF1 is an
impo an con ibu ion ac o ha sus ains he ansc ip ional exp es-
sion o he glycoly ic machine y (Semenza e al., 1994), i s inhibi ion
a e ROS a enua ion con ibu es o a dec ease in he glycoly ic lux
(Jimenez-Blasco e al., 2020). Impo an ly, he impai ed glycoly ic lux
a ec s he elease o lac a e, which canno be p ope ly aken up by
neu ons, acco ding o he as ocy e-neu ons lac a e shu le model
(Machle e al., 2016; Pelle in and Magis e i, 1994; Suzuki e al.,
2011). E en ually, his scena io causes neu onal dys unc ion ha , upon
THC adminis a ion is ma e ialized as a loss o social in e ac ion
(Jimenez-Blasco e al., 2020). Indeed, in ace eb al injec ion o lac a e
e icien ly escues he loss o social in e ac ion caused by ch onic THC
adminis a ion in mice (Jimenez-Blasco e al., 2020), in good ag eemen
wi h p e ious esul s showing an idep essan e ec s by pe iphe al
adminis a ion o lac a e (Ca a d e al., 2018). These indings indica e
ha , by dec easing he na u al high abundance o mROS, m CB
1
e-
cep o pe sis en ac i a ion impai s as oglial glucose me abolism
impac ing on neu onal ac i i y, which leads o a pa hological ci cum-
s ance like loss o social in e ac ion.
4. Concluding ema ks and u u e pe spec i es
In conclusion, his ocused e iew aims o con ibu e o ou be e
unde s anding on he molecula mechanisms esponsible o he physi-
ological gene a ion and signaling oles o mROS by as ocy es, ac-
co ding o in i o wo k. Ob iously, gi en he pleio opic e ec s o ROS,
he e would be many o he speci ic a ge s ha could accoun o he
p ese a ion o cellula , issula and o ganismal unc ions by as ocy ic
mROS, which su ely will be elucida ed in he u u e. By ma ching mo-
lecula mROS a ge s wi h neu onal unc ions, i will be possible o
dissec ou speci ic pa hways ha link molecules wi h o ganismal
highe -o de beha io . Fu he mo e, la ge p oduc ion o sus ained
mROS may bo h be bene icial o dele e ious, a balance ha is de e -
mined by he cellula ype and he me abolic condi ion (Fig. 1). In e -
es ingly, as ocy ic mROS u he inc ease du ing physiological hypoxia
as pa o a possible pO
2
sensing mechanism (Angelo a e al., 2015).
The e o e, accu a ely unde s anding how high physiological mROS
le els exe s bene icial e ec s is impo an when designing an ioxidan
D. Jimenez-Blasco e al.
Neu obiology o Disease 184 (2023) 106199
4
s a egies o comba diseases in which bu s s o mROS -likely happening
in neu ons- a e dele e ious, since sca enging o such sudden inc eases in
mROS indisc imina ely -i.e., a ec ing as ocy ic mROS- may pa adoxi-
cally esul in loss o an ioxidan p e en ion a he long e m conse-
quen ly causing delayed neu al damage. Fu u e wo k would be
necessa y o design cell-speci ic he apeu ic s a egies o sca enge
mROS in neu ons ansien ly wi hou a ec ing he na u al p oduc ion o
mROS by neighbo as ocy es.
Funding in o ma ion
Au ho s we e suppo ed by he Nex Gene a ionEU/PRTR and
Agencia Es a al de In es igaci´
on (10.13039/501100011033; PID2019-
105699RB-I00; PID2022-138813OB-I00; PDC2021–121013-I00;
RED2018–102576-T o JPB; RED2022–134407-T o AA); Plan Nacional
de D ogas (2020I028 o JPB); Ins i u o de Salud Ca los III (CB16/10/
00282 o JPB; PI21/00727; PMP22/00084 and RD21/0006/0005 co-
unded by he Eu opean Union, o AA); Ma ie Sklodowska-Cu ie Ac-
ion HORIZON-MSCA-2021-DN-01 (101072759 o JPB and AAP), and
Jun a de Cas illa y Le´
on (CS/151P20 co- unded by P.O. FEDER o AA;
Apoyo Regional a la Compe i i idad Emp esa ial, ICE 04/18/LE/0017
o JPB, and Escale a de Excelencia CLU-2017-03 o JPB and AA). DJB is
a ecipien o a Juan de la Cie a-Inco po aci´
on con ac
(IJC2020–044230-I).
Au ho con ibu ion
JPB concep ualiza ion. DJB Da a cu a ion, W i ing - o iginal d a .
JPB and AA w i ing - e iew & edi ing.
Decla a ion o Compe ing In e es
The au ho s decla e ha hey ha e no con lic s o in e es wi h he
con en s o his a icle.
Da a a ailabili y
No da a was used o he esea ch desc ibed in he a icle.
Re e ences
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