The ca o id body oxygen senso
Lin Gao
1,2,3
, Alejand o Mo eno-Domínguez
1,2,3
,
Pa icia O ega-Sáenz
1,2,3
and José López-Ba neo
1,2,3
Ca o id body (CB) chemo ecep o glomus cells sense hypoxia
h ough he inhibi ion o plasmalemmal K
+
channels, which
leads o he opening o Ca
2+
channels, Ca
2+
in lux, and
neu o ansmi e elease. The mechanism o O
2
sensing and
he egula ion o memb ane ion channels by O
2
ha e emained
unde ined and a subjec o deba e. He e, we summa ize he
molecula pa hway ha unde lies acu e O
2
sensing in he CB.
This p ocess does no ely on a single-molecule O
2
senso
exp essed in glomus cells bu a he on HIF2
a
-dependen
gene ically specialized mi ochond ia ha can de ec changes
in O
2
ension, wi hin physiological anges, and gene a e
biochemical signals ha egula e memb ane ion channels. The
acu e O
2
-sensing pa hway in glomus cells could p o ide new
a ge s o espi a o y and ca dio ascula pha macology.
Add esses
1
Ins i u e o Biomedicine o Se ille (IBiS), Uni e si y Hospi al “Vi gen
del Rocío”/CSIC/Uni e si y o Se ille, Se ille, Spain
2
Depa men o Medical Physiology and Biophysics. School o Medi-
cine, Uni e si y o Se ille, Se ille, Spain
3
CIBERNED, Mad id, Spain
Co esponding au ho : López-Ba neo, José (lba [email p o ec ed])
Cu en Opinion in Neu obiology 2025, 92:103022
This e iew comes om a hemed issue on In e ocep ion 2025
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A ailable online 22 Ap il 2025
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In oduc ion
The ca o id body (CB) is he p o o ypical acu e
oxygen (O
2
)-sensing o gan in mammals, playing an
essen ial ole in ini ia ing apid adap i e ca dio espi-
a o y e lexes, such as hype en ila ion and inc eased
ca diac ou pu , igge ed by low O
2
ension (hypoxia).
O
2
sensing is an in insic p ope y o neu al c es -
de i ed chemo ecep o glomus cells, which a e he
mos abundan cell ype in he CB. These cells a e in
close con ac wi h a dense ne wo k o enes a ed
capilla ies and a e inne a ed by senso y ibe s o he
pe osal ganglion, which connec s o b ains em espi-
a o y and au onomic cen e s [1].
Glomus cells a e exci able, p esynap ic-like elemen s
ha con ain O
2
-sensi i e K
þ
channels. The inhibi ion o
hese channels du ing hypoxia leads o depola iza ion,
Ca
2þ
in lux, and he exocy o ic elease o neu o ans-
mi e s [2e4]. Glomus cells a e highly dopamine gic
bu also con ain a a ie y o o he ansmi e s ha play
a modula o y au oc ine and pa ac ine ole. ATP is he
main exci a o y ansmi e , ac ing on iono opic pu i-
ne gic ecep o s loca ed in he a e en senso y e mi-
nals [2]. While he basic elec ophysiological and
neu osec e o y cha ac e is ics suppo ing he senso y
p ope ies o glomus cells a e well es ablished, he
molecula mechanisms unde lying O
2
sensing and he
modula ion o memb ane ion channels by O
2
ha e
emained elusi e. As a esul , hese mechanisms we e
ep esen ed by ques ion ma ks in a summa y o glomus
cell unc ion published in his jou nal in 2003 [5*].
The iden i y o he O
2
senso in he CB has been a
subjec o deba e [6,7], wi h se e al p omising candi-
da es, including enzymes and ecep o s di ec ly o
indi ec ly egula ed by O
2
ension, discussed in he
li e a u e [5,7e12]. Howe e , s udies using knockou
mouse models, which lack he genes encoding he pu-
a i e O
2
-sensing molecules (e.g. heme oxygenase 2,
cys a hionine-
g
-lyase, AMP kinase, o ol ac o y ecep o
78), ha e shown ha al hough hese molecules may
ha e ele an unc ional oles, none a e essen ial o
acu e O
2
sensing in he CB [5*,13e17].
Fo he pas ew yea s, he combined use o gene ically
modi ied mice, compa a i e gene exp ession analyses,
and obus single-cell moni o ing o esponsi eness o
hypoxia has enabled us o comple e he desc ip ion o
he molecula pa hway ha unde lies, and is indis-
pensable o , CB acu e O
2
-sensing. This p ocess does
no depend on a single-molecule O
2
senso exp essed in
glomus cells, bu a he on gene ically specialized
mi ochond ia ha can de ec hypoxia wi hin he phys-
iological ange and gene a e biochemical signals ha
egula e memb ane ion channels [18**,19*,20**,21**,
22*].
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Mi ochond ial complex I-dependen
gene a ion o hypoxic signals and
modula ion o ion channel unc ion
I has long been known ha mi ochond ial inhibi o s a e
po en ac i a o s o he CB [23,24*] and ha some
mi ochond ial pa ame e s in glomus cells a e modula ed
by O
2
ension [25*,26e28*]. We demons a ed ha ,
simila o hypoxia [1], ac i a ion o CB glomus cells by
mi ochond ial inhibi o s equi es ex acellula Ca
2þ
in lux and ha o enone, a selec i e inhibi o o mi o-
chond ial complex I (MCI), no only mimics hypoxia bu
in i s p esence he cells become insensi i e o hypoxia
[24*]. These obse a ions sugges ed ha mi ochond ia
may modula e memb ane elec ical ac i i y in glomus
cells and ha acu e O
2
sensing could depend on MCI
unc ion. To es hese hypo heses, we used a mouse
model wi h condi ional gene ic dis up ion o MCI,
c ea ed by abla ion o he Ndu s2 gene, which encodes a
subuni o he ca aly ic co e o MCI necessa y o co-
enzyme Q (CoQ) binding and o enone blockade
[18**,29]. MCI is a mul ime ic NADH dehyd ogenase
ha ans e s elec ons om NADH o CoQ, gene a ing
CoQH
2
, which in u n se es as he subs a e o mi o-
chond ial complex III (MCIII). This eac ion is coupled
o p o on pumping, whe e MCI anspo s H
þ
om he
mi ochond ial ma ix o he in e memb ane
space (IMS).
NDUFS2-de icien mice, in which glomus cells lack
MCI ac i i y, can su i e o se e al mon hs, likely
due o up egula ion o glycolysis [18**,19*,22*].
These cells main ain no mal mo phology, elec ical
p ope ies, and neu osec e o y ac i i y, wi h no mal
dopamine con en in hei sec e o y esicles,
sugges ing ha hey e ain undamen al physiological
unc ions. Howe e , hypoxia-induced exocy o ic ca e-
cholamine elease is comple ely abolished in MCI-
de icien glomus cells, al hough hei sec e o y
esponse o hype capnia and o he s imuli emains
in ac (Figu e 1aed). In pa allel, hypoxia-induced
modula ion o memb ane ionic cu en s and in-
c eases in cy osolic Ca
2þ
we e also elimina ed in
MCI-de icien glomus cells [18**,19*]. These ind-
ings led us o p opose a dynamic mi ochond ial- o-
memb ane signaling (MMS) model o acu e O
2
sensing, which is based on he ole o O
2
as an
essen ial subs a e o cy och ome coxidase (CCO) in
mi ochond ial complex IV (MCIV) and he e e s-
ibili y o p eceding eac ions in he mi ochond ial
elec on anspo chain (ETC) (Figu e 2a). In he
MMS model, a dec ease in O
2
ension du ing hypoxia
leads, ia mass ac ion, o a backlog o subs a es in he
educed s a e, a o ing he p oduc ion o supe oxide
anion (con e ed o H
2
O
2
by supe oxide dismu ase)
in he mi ochond ial IMS. The inc ease in CoQH
2
esul s in a slowdown o MCI ac i i y and he accu-
mula ion o NADH. Following equilib a ion wi h he
cy osol, NADH and H
2
O
2
in e ac wi h memb ane ion
channels, igge ing cell depola iza ion and ansmi e
elease [18**,30**].
Suppo o he MMS model has come om mic o-
luo ime ic analyses o single glomus cells, which
showed g aded inc eases in NADH and H
2
O
2
le els in
esponse o a ious le els o hypoxia. Mo eo e , hese
signals we e abolished in MCI-de icien glomus cells
(Figu e 2b) [19*]. Bo h NADH and H
2
O
2
a e well-
known ion channel modula o s [31,32], and in glomus
cells, hey mimic and a enua e he e ec s o hypoxia on
backg ound and ol age-dependen K
þ
cu en s [18**].
Howe e , hypoxia-induced memb ane depola iza ion in
glomus cells does no appea o depend on a speci ic
class o O
2
- egula ed K
þ
channels bu a he on he
in e ac ion o NADH and H
2
O
2
wi h se e al channel
ypes. Fo example, TASK1 and TASK3 K
þ
channels,
which a e highly exp essed in glomus cells [20**,33**],
ha e been sugges ed o media e he backg ound K
þ
cu en whose inhibi ion by hypoxia igge s memb ane
depola iza ion [28,34]. Ne e heless, glomus cells om
mice wi h gene ic abla ion o Task1 and Task3 s ill exhibi
no mal sec e o y esponses o hypoxia. These indings
sugges ha o he ion channels, egula ed by NADH
and/o H
2
O
2
dpossibly ol age-ga ed K
þ
channels,
which also con ibu e o se ing he es ing po en-
ialdcompensa e o he absence o TASK1 and TASK3
channels [35*].
The MMS model (Figu e 2a) assumes ha he essen ial
ole o MCI in acu e O
2
sensing is o gene a e he signals
ha egula e ion channel unc ion, a he han di ec ly
sensing changes in O
2
ension. In ag eemen wi h his
concep , ansgenic exp ession o NDI1, a single-
molecule al e na i e yeas NADH/CoQ oxido educ ase
ha is s uc u ally un ela ed o he 45-subuni
mammalian MCI, comple ely escues he O
2
-sensing
unc ion o MCI-de icien glomus cells [22*]. NDI1
exp ession es o es hypoxia-induced NADH and H
2
O
2
signals (Figu e 2b) and he sec e o y esponse o glomus
cells o hypoxia. Mice-exp essing NDI1 also eco e he
hypoxic en ila o y esponse (HVR), a sys emic e lex
dependen on CB unc ion [1], which is selec i ely los
in MCI-de icien mice (Figu e 2c) [22*]. Since NDI1
canno pump p o ons, hese obse a ions indica e ha
he dynamic changes in NADH dehyd ogenase ac i i y,
induced by he dec ease in O
2
a ailabili y du ing hyp-
oxia (Figu e 2a), a e essen ial o he acu e O
2
-sensing
pa hway in CB glomus cells. Addi ional suppo o he
MMS model o acu e O
2
-sensing was ecen ly p o ided
by expe imen s in mice wi h gene ic abla ion o MCIII
in glomus cells. These MCIII-de icien mice exhibi
comple e absence o he HVR, while hey ha e no mal
en ila o y esponses o hype capnia. Mo eo e , MCIII-
de icien glomus cells, wi h an in e up ed ETC, a e
insensi i e o hypoxia and cyanidedan MCIV
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blocke dbu ha e no mal sec e o y esponses o hy-
pe capnia and o he s imuli [36].
Gene ically specialized mi ochond ia o
physiological acu e O
2
-sensing
CB glomus cells a e ex ao dina ily sensi i e o
hypoxia as hey can de ec changes in O
2
ension in hei
su ounding en i onmen a le els sligh ly below
80e90 mmHg [13,35]. In all issues s udied, he e-
po ed Km alues o CCO o O
2
a e w1 mmHg o lowe .
The e o e, e en assuming a ma ked O
2
g adien be-
ween he ex acellula medium and mi ochond ia, he
O
2
le els ha ac i a e glomus cells a e clea ly abo e
sa u a ion o MCIV. These ac s sugges ha glomus
cells possess an a ypical mi ochond ial ETC capable o
esponding o luc ua ions in high le els o O
2
ension.
In suppo o his idea, ansc ip omic s udies
[20**,33**] ha e iden i ied a “signa u e gene ic p o-
ile” cha ac e is ic o O
2
-sensi i e CB cells, dis in-
guishing hem om o he neu al c es -de i ed
cellsde.g. sympa he ic neu ons in he supe io ce i-
cal gangliond, which a e O
2
-insensi i e [37**]. Among
he ansc ip s highly exp essed in CB cells a e hose
coding o py u a e ca boxylaseda mi ochond ial
anaple o ic enzyme ha main ains he supply o sub-
s a es o mi ochond ial ETCd[38], wo MCIV co e
subuni iso o ms (COX4I2 and COX8B), and wo
addi ional ETC subuni s belie ed o be associa ed wi h
MCIV (NDUFA4L2 and HIGD1C) [20**,33**,39**].
No ably, he exp ession o Cox4i2, Cox8b, and Ndu a4l2
depends on he cons i u i e ansc ip ional ac i i y o
HIF2
a
[21**,40*], which is highly exp essed in CB
Figu e 1
Reco ding o sec e o y ac i i y in single ca o id body glomus cells by ampe ome y (a) and examples o single sec e o y e en s (b).(c,d) Selec i e
aboli ion o he sec e o y esponse o hypoxia in glomus cells om mi ochond ial complex I (MCI)-de icien mice. Ac i a ion o he cells by hype capnia
(CO
2
) emains unal e ed.
Acu e oxygen sensing Gao e al. 3
www.sciencedi ec .com Cu en Opinion in Neu obiology 2025, 92:103022
glomus cells unde no mal (no moxic) condi ions
[20**,33**,41]. Mo eo e , Higd1c con ains se e al pu-
a i e hypoxia- esponsi e elemen s in i s p omo e
egion, and i s exp ession in he CB also seems o
depend on HIF2
a
[40*]. Exp ession o Epas1d he
HIF2
a
-encoding genedis equi ed o CB emb yonic
de elopmen [42*] and dis up ion o Epas1 in adul hood
s ongly inhibi s glomus cell esponsi eness o hypoxia
[21**] and he HVR [21**,43*]. Simila esul s a e
ob ained by abla ion o ei he he Cox4i2 gene [21*]o ,
wi h less po ency, he Higd1c gene [39**]. Howe e ,
Ndu a4l2 de iciency does no al e glomus cell sensi i i y
o hypoxia o he HVR [21**]. These indings sugges
ha much o he O
2
-sensing unc ion o glomus cell
MCIV depends on he HIF2
a
-dependen exp ession o
COX4I2 and HIGD1C.
COX4, a nuclea -encoded p o ein, is one o he 13 sub-
uni s o ming he ca aly ic co e o CCO [44]. I is loca ed
a he pe iphe y o MCIVand consis s o a helix spanning
he mi ochond ial inne memb ane, wi h N- e minus
(ma ix) and C- e minus (IMS) domains. In mammals,
COX4 has wo iso o ms: COX4I1, which is widely
exp essed in all issues, and COX4I2, which is issue-
speci ic and mainly exp essed in he lung, ascula
smoo h muscle, and he CB [45*]. In e es ingly, issue-
speci ic exp ession o Cox4i2 mRNA is induced by hyp-
oxia h ough he up egula ion o hypoxia inducible ac o s
Figu e 2
b
50 a.u.
Hx Hx
IMS H2O2
Hx Hx
Hx Hx
2 min
0.005
Hx Hx
400/484
Hx Hx
2 min
Hx Hx
NADH
hypoxia-induced mi ochond ial signals
wild- ype
MCI-KO
MCI-KO/Ndi1
c
hypoxic en ila o y esponse
5 min
100
150
200
250
300
b ea hs/min
21%
O
2
ension
wild- ype
MCI-de icien (MCI-KO)
MCI-de icien / ansgenic Ndi1 (MCI-KO/Ndi1)
a
MCIV
MCI CoQH
2
MCIII
MCII
O
2
H
2
O
(Hx)
dynamic changes in ETC induced by hypoxia
IMM
Cy C
NADH H
2
O
2
OMM
IMS
Ma ix
H
2
O
2
10%
Cu en Opinion in Neu obiology
(a) Scheme o he dynamic changes in mi ochond ial elec on anspo chain (ETC) induced by hypoxia ( ed a ows and symbols). OMM: ou e mi o-
chond ial memb ane; IMS: in e memb ane space; IMM: inne mi ochond ial memb ane. (b) Changes in he in acellula le els o NADH and IMS H
2
O
2
du ing epea ed exposu e o hypoxia moni o ed by mic o luo ime y in single glomus cell om wild ype mice, mi ochond ial complex I (MCI)-de icien mice
and MCI-de icien mice exp essing ansgenic yeas NDI1. (c) Hypoxic en ila o y esponse o he h ee mice s ains indica ed in (b).
4In e ocep ion 2025
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(HIFs) and o he ansc ip ion ac o s [21**,46*,47].
Al hough he di e en ial unc ional cha ac e is ics o
COX4 iso o ms a e no comple ely unde s ood, i is
known ha he p esence o COX4I2 ins ead o COX4I1
ma kedly accele a es CCO ac i i y, possibly because his
subuni is less suscep ible o allos e ic nega i e modula-
ion by ATP [45*]. In pe meabilized HEK cells, exp es-
sion o COX4I2, ins ead o COX4I1, dec eases he a ini y
o CCO o O
2
. Howe e , he epo ed Km aluesdO
2
ensions o 0.5 and 1 mmHg in mi ochond ia exclusi ely
exp essing COX4I1 o COX4I2, espec i elyd[48], a e
much lowe han he O
2
ension le els ha modula e
glomus cell unc ion. Simila e ec s ha e been epo ed
o HIGD1C exp essed in HEK cells [39**], which sug-
ges s ha , besides he po en ial e ec s o COX4I2 and
HIGD1C on he binding a ini y o CCO o O
2
,o he
local ac o sdsuch as he a e o elec on anspo o he
in e ac ions o COX4I2 and HIGD1C wi h NDUFA4L2
and/o COX8Bdin luence he O
2
sensi i i y o
mi ochond ial CCO in glomus cells. The p esence o
glomus cell-speci ic MCIV subuni iso o ms may hinde
he accessibili y o O
2
o he ca aly ic cen e (CuB/heme
a
3
) and in his manne dec ease he appa en a ini y o
he enzyme [21**,48,49]. In mi ochond ia wi h an
accele a ed ETC and high CCO u no e [20**,44], a
dec ease in O
2
a ailabili y du ing hypoxia could cause a
misma ch be ween subs a es (elec ons and O
2
), leading
o an accumula ion o educed in e media es in he ETC
and he gene a ion o hypoxia-induced mi ochon-
d ial signals.
The acu e O
2
-sensing pa hway in glomus cells is
schema ically summa ized in Figu e 3.I dependson
HIF2
a
-dependen gene ically specialized mi ochon-
d ia, wi h high me abolic ac i i y and high sensi i i y o
dec eases in O
2
ension. Unde hypoxic condi ions, he
ela i e lack o O
2
causes a dec ease in CCO ac i i y
(s ep 1), leading o an accumula ion o educed cy o-
ch ome c and a backlog o educed in e media es in he
ETC (s ep 2). The hypoxia-induced dynamic changes
in he ETC p omo e he o ma ion o H
2
O
2
in he IMS
andaccumula iono NADHin hema ix(s ep3).
A e equilib a ion wi h he cy osol, hese mi ochon-
d ial signals inhibi K
þ
channels (s ep 4), leading o cell
depola iza ion, opening o Ca
2þ
channels (s ep 5), and
elease o ansmi e s ha ac i a e a e en ibe s
(s ep6).I couldbespecula ed ha inglomuscells,
mi ochond ia specialized o acu e O
2
-sensing a e
loca ed nea he memb ane, close o ion channels,
o ming “O
2
-sensing mic odomains”. Suppo ing his
idea, elec on mic oscopy s udies e eal ha he
dis ance be ween mi ochond ia and he plasma mem-
b aneinglomuscellsissho e hanino he cell
ypes [50].
Figu e 3
Cu en Opinion in Neu obiology
Acu e oxygen-sensing pa hway in ca o id body glomus cells. IMS, mi ochond ial in e memb ane space. See ex o explana ion.
Acu e oxygen sensing Gao e al. 5
www.sciencedi ec .com Cu en Opinion in Neu obiology 2025, 92:103022
Conclusions
CB glomus cells a e he p ima y acu e O
2
-sensing ele-
men s in he body and a e essen ial o igge ing apid
adap i e esponses, such as hype en ila ion and
inc eased ca diac ou pu , o hypoxia. Unde s anding o
he mechanisms unde lying O
2
sensing by glomus cells
has signi ican ly p og essed in he las 20 yea s. Recen
da a indica e ha he CB O
2
senso is no a single-
molecule s uc u e bu a he an in ica e signaling
pa hway ha elies on specialized mi ochond ia, la gely
dependen on he cons i u i e high exp ession o HIF2
a
[21**,40*,51**]. These mi ochond ia can de ec
changes in O
2
ension wi hin physiological anges and
signal memb ane ion channels o modula e glomus cell
ansmi e elease. Simila O
2
-sensing mechanisms
appea o ope a e in cells o he ad enal medulla and in
sys emic and pulmona y ascula smoo h muscle, which
also espond acu ely o hypoxia [18**,52,53*,54**].
Beyond i s pa hophysiological signi icance, he acu e O
2
-
sensing pa hway based on mi ochond ia- o-memb ane
signaling p o ides new possibili ies in espi a o y and
ca dio ascula pha macology, including he po en ial
he apeu ic applica ion o NADH mime ics, mi ochon-
d ial me abolism modula o s, and HIF inhibi o s.
Au ho s’con ibu ion
All he au ho s con ibu ed o he design o he a icle
and he w i ing o he d a .
J.L.-B. coo dina ed he w i ing o he pape .
Decla a ion o compe ing in e es
The e a e no compe ing in e es s o disclose.
Acknowledgemen s
This esea ch was suppo ed by he Spanish Minis ies
o Science and Inno a ion and Heal h (G an s PID2022-
138131OB-I00, and PID2023-146862OB-100 unded by
MCIN/AEI/10.13039/501100011033 o J.L.-B., L.G.
A.M.-D. and P.O.-S) and he Eu opean Resea ch Council
(ERC Ad anced G an PRJ201502629).
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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ha e been highligh ed as:
* o special in e es
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5
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glomus cells.Cu Opin Neu obiol 2003, 13:493–499.
A b ie e iew on ca o id body oxygen sensing, summa izing he s a e
o he ield and he ongoing deba e in he li e a u e on he na u e o he
oxygen senso om wen y yea s ago.
6. Kemp PJ: De ec ing acu e changes in oxygen: will he eal
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body: a a lebag o molecula mechanisms.J Physiol 2018,
596:2969–2976.
8. Williams SE, Woo on P, Mason HS, Bould J, Iles DE, Ricca di D,
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2093–2097.
9. Peng YJ, Nandu i J, Raghu aman G, Sou annaki i D,
Gadalla MM, Kuma GK, Snyde SH, P abhaka NR: H
2
S medi-
a es O
2
sensing in he ca o id body.P oc Na l Acad Sci U S A
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Chen X, Fox AP, Vignane T, Filipo ic MR, P abhaka NR: Hyp-
oxia sensing equi es H
2
S-dependen pe sul ida ion o ol-
ac o y ecep o 78.Sci Ad 2023, 9, ead 3026.
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egula ion by AMPK: he ou e o hypoxia- esponse coupling
in he ca o id body and pulmona y a e y.Ann N Y Acad Sci
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ac i a ed by lac a e.Na u e 2015, 527:240–244.
13. O ega-Saenz P, Pascual A, Gomez-Diaz R, Lopez-Ba neo J:
Acu e oxygen sensing in heme oxygenase-2 null mice.J Gen
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14. Wang J, Hogan JO, Wang R, Whi e C, Kim D: Role o
cys a hionine-gamma-lyase in hypoxia-induced changes in
TASK ac i i y, in acellula [Ca
2+
] and en ila ion in mice.
Respi Physiol Neu obiol 2017, 246:98–106.
15. Mahmoud AD, Lewis S, Ju icic L, Udoh UA, Ha mann S,
Jansen MA, Ogunbayo OA, Puggioni P, Holmes AP, Kuma P,
e al.: AMP-Ac i a ed p o ein kinase de iciency blocks he
hypoxic en ila o y esponse and hus p ecipi a es hypo-
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16. To es-To elo H, O ega-Saenz P, Macias D, Omu a M, Zhou T,
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o id body unc ion in y osine hyd oxylase condi ional
Ol 78 knockou mice.Func ion (Ox ) 2024, 5, zqae010.
18
**
.Fe nandez-Ague a MC, Gao L, Gonzalez-Rod iguez P,
Pin ado CO, A ias-Mayenco I, Ga cia-Flo es P, Ga cia-
Pe ganeda A, Pascual A, O ega-Saenz P, Lopez-Ba neo J:
Oxygen sensing by a e ial chemo ecep o s depends on
mi ochond ial complex I signaling.Cell Me ab 2015, 22:
825–837.
This pape demons a es ha gene ic dis up ion o mi ochond ial
complex I in y osine hyd oxylase-posi i e ca o id body glomus cells
and ch oma in cells in he ad enal medulla selec i ely abolishes hei
esponsi eness o hypoxia. Responses o o he s imuli, such as hy-
pe capnia o hypoglycemia, emain unal e ed. The indings p o ided
expe imen al suppo o he o mula ion o a mi ochond ial- o-
memb ane signaling model o acu e oxygen sensing.
19
*
.A ias-Mayenco I, Gonzalez-Rod iguez P, To es-To elo H,
Gao L, Fe nandez-Ague a MC, Bonilla-Henao V, O ega-
Saenz P, Lopez-Ba neo J: Acu e O
2
sensing: ole o coenzyme
6In e ocep ion 2025
Cu en Opinion in Neu obiology 2025, 92:103022 www.sciencedi ec .com
QH
2
/Q a io and mi ochond ial ROS compa men aliza ion.
Cell Me ab 2018, 28:145–158 e144.
This s udy demons a es he dose-dependen gene a ion o hypoxia-
induced mi ochond ial signals (NADH and H
2
O
2
) in ca o id body
glomus cells and he aboli ion o hese signals in mi ochond ial com-
plex I-de icien cells. Hypoxia p oduces compa men alized changes in
H
2
O
2
, wi h an inc ease in he mi ochond ial in e memb ane space and
a dec ease in he ma ix.
20
**
.Gao L, Bonilla-Henao V, Ga cia-Flo es P, A ias-Mayenco I,
O ega-Saenz P, Lopez-Ba neo J: Gene exp ession analyses
e eal me abolic speci ica ions in acu e O
2
-sensing chemo-
ecep o cells.J Physiol 2017, 595:6091–6120.
Mic oa ay gene exp ession analysis was conduc ed o compa e h ee
o gans o he same neu al c es emb yonic o igin, bu wi h a ying
sensi i i y o hypoxia in adul hood: he ca o id body (high sensi i i y),
ad enal medulla (medium sensi i i y), and supe io ce ical ganglion
(low sensi i i y). Se e al mi ochond ial genes we e ound o be highly
speci ic o ca o id body cells.
21
**
.Mo eno-Dominguez A, O ega-Saenz P, Gao L, Colinas O,
Ga cia-Flo es P, Bonilla-Henao V, A agones J, Hu emann M,
G ossman LI, Weissmann N, e al.: Acu e O
2
sensing h ough
HIF2alpha-dependen exp ession o a ypical cy och ome ox-
idase subuni s in a e ial chemo ecep o s.Sci Signal 2020, 13.
This pape demons a es ha he sensi i i y o glomus cells o hypoxia
depends on he cons i u i ely high exp ession o HIF2
a
. Dele ion o
Epas1 — he HIF2
a
-encoding gene—in adul glomus cells selec i ely
abolishes bo h he cells’ esponsi eness o hypoxia and he sys emic
hypoxic en ila o y esponse. HIF2
a
is essen ial o he exp ession o
se e al a ypical mi ochond ial complex IV subuni iso o ms in mouse
glomus cells. No ably, one iso o m o COX4 (COX4I2) is absolu ely
equi ed o con e hypoxia sensi i i y o glomus cells wi hin physio-
logical O
2
ension le els.
22
*
.Jimenez-Gomez B, O ega-Saenz P, Gao L, Gonzalez-
Rod iguez P, Ga cia-Flo es P, Chandel N, Lopez-Ba neo J:
T ansgenic NADH dehyd ogenase es o es oxygen egula-
ion o b ea hing in mi ochond ial complex I-de icien mice.
Na Commun 2023, 14:1172.
Exp ession o yeas NADH dehyd ogenase NDI1 in mouse glomus
cells lacking mi ochond ial complex I (MCI) ully es o es he elec on
anspo chain and hypoxia esponsi eness a bo h cellula and sys-
emic le els. This expe imen demons a es ha MCI is no di ec ly
in ol ed in O
2
sensing; howe e , dynamic changes in NADH dehy-
d ogenase ac i i y a e essen ial o glomus cell esponsi eness o
hypoxia.
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cep o esponses o O
2
and CO
2
by oligomycin and by an i-
mycin A.Am J Physiol 1982, 242:C200–C206.
24
*
.O ega-Saenz P, Pa dal R, Ga cia-Fe nandez M, Lopez-
Ba neo J: Ro enone selec i ely occludes sensi i i y o hyp-
oxia in a ca o id body glomus cells.J Physiol 2003, 548:
789–800.
This s udy shows ha o enone and o he inhibi o s o mi ochond ial
elec on anspo chain ac i a e glomus cells in an ex e nal Ca
2+
-
dependen manne . In he p esence o o enone, glomus cells become
insensi i e o hypoxia.
25
*
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This seminal s udy demons a ed ha se e al mi ochond ial pa ame-
e s in glomus cells a e egula ed by O
2
ension.
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po en ial and [Ca
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]
i
in ype I cells isola ed om he abbi
ca o id body.J Physiol 1992, 450:33–61.
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28
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unc ion in a a e ial chemo ecep o cells.J Physiol 2013,
591:3549–3563.
De ailed s udy on he egula ion o mi ochond ial pa ame e s in glomus
cells by O
2
ension.
29. Kashani-Poo N, Zwicke K, Ke sche S, B and U: A cen al
unc ional ole o he 49-kDa subuni wi hin he ca aly ic co e
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30
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elusi e mechanism.Cell Me ab 2015, 22:753–754.
An insigh ul discussion on he signi icance o s udies in ol ing gene ic
dis up ion o mi ochond ial complex I o ad ancing ou unde s anding
o acu e oxygen sensing by ca o id body glomus cells.
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sc ip ome analysis o mouse ca o id body glomus cells.
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This de ailed ansc ip omic analysis o ca o id body glomus cells
e ealed high exp ession le els o se e al enzymes, ecep o s, and
a ypical subuni iso o ms o mi ochond ial complex IV.
34. Kim D, Ca anaugh EJ, Kim I, Ca oll JL: He e ome ic TASK-1/
TASK-3 is he majo oxygen-sensi i e backg ound K
+
chan-
nel in a ca o id body glomus cells.J Physiol 2009, 587:
2963–2975.
35
*
.O ega-Saenz P, Le i sky KL, Ma cos-Alma az MT, Bonilla-
Henao V, Pascual A, Lopez-Ba neo J: Ca o id body chemo-
senso y esponses in mice de icien o TASK channels.J Gen
Physiol 2010, 135:379–392.
This s udy demons a es ha ca o id body glomus cells de icien in
TASK1 and TASK3 channels exhibi no mal sec e o y esponses o
hypoxia. The implica ions o hese indings o he physiology o glomus
cells a e discussed in de ail.
36. Cabello-Ri e a D, O ega-Saenz P, Gao L, Munoz-Cabello AM,
Bonilla-Henao V, Schumacke PT, Lopez-Ba neo J: Oxygen
egula ion o b ea hing is abolished in mi ochond ial com-
plex III-de icien a e ial chemo ecep o s.P oc Na l Acad Sci U
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**
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An au ho i a i e discussion o da a om se e al ecen publica ions ha
de ail he gene ic me abolic p o ile speci ic o acu e oxygen-sensing
cells, wi h a pa icula ocus on ca o id body glomus cells.
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mi ochond ial HIGD1C p omo es oxygen sensi i i y in ca o id
body chemo ecep o s.Eli e 2022, 11.
This s udy in es iga es he ole o HIGD1C, a mi ochond ial p o ein
associa ed wi h complex IV, in ca o id body (CB) acu e oxygen sensing.
I e eals ha HIGD1C is highly exp essed in he CB compa ed o o he
iso o ms, such as HIGD1A. Abla ion o he gene encoding HIGD1C
diminishes he sensi i i y o CB cells o hypoxia. Fu he mo e, he s udy
shows ha bo h CB sensi i i y o hypoxia and he hypoxic en ila o y
esponse a e impai ed in COX4I2-de icien mice. Addi ionally, he
combined he e ologous exp ession o he wo MCIV subuni iso o ms,
COX4I2 and HIGD1C, is epo ed o dec ease he a ini y o cy o-
ch ome coxidase o oxygen.
40
*
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Ba neo J: Cons i u i e exp ession o Hi 2alpha con e s acu e
O
2
sensi i i y o ca o id body glomus cells.Ad Exp Med Biol
2023, 1427:153–162.
Demons a ion ha he exp ession o se e al genes encoding mi o-
chond ial complex IV subuni s, including Higd1c, in glomus cells de-
pends on HIF2
a
.
41. Tian H, Hamme RE, Ma sumo o AM, Russell DW, McKnigh SL:
The hypoxia- esponsi e ansc ip ion ac o EPAS1 is
essen ial o ca echolamine homeos asis and p o ec ion
agains hea ailu e du ing emb yonic de elopmen .Genes
De 1998, 12:3320–3324.
42
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Lopez-Ba neo J, Johnson RS: HIF-2alpha is essen ial o ca-
o id body de elopmen and unc ion.Eli e 2018, 7, e34681.
Emb yonic abla ion o he gene encoding HIF2
a
leads o a ophy o he
ca o id body (CB). Mice wi h CB a ophy exhibi an almos comple e
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www.sciencedi ec .com Cu en Opinion in Neu obiology 2025, 92:103022
loss o he hypoxic en ila o y esponse, along wi h al e a ions in o he
ele an physiological and me abolic pa ame e s.
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Douglas G, Ra nayaka I, Robbins PA, Pugh CW, Buckle KJ,
e al.: Regula ion o en ila o y sensi i i y and ca o id body
p oli e a ion in hypoxia by he PHD2/HIF-2 pa hway.J Physiol
2016, 594:1179–1195.
Down egula ion o he gene encoding HIF2
a
esul s in a dec ease in
he hypoxic en ila o y esponse while o e exp ession o HIF2
a
in-
duces ca o id body hype ophy.
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unc ion o mammalian cy och ome c oxidase.Mi ochond ion
2015, 24:64–76.
45
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Somme N, Sande son TH, Tos M, e al.: Cy och ome c oxidase
subuni 4 iso o m 2-knockou mice show educed enzyme
ac i i y, ai way hypo eac i i y, and lung pa hology.FASEB J
2012, 26:3916–3930.
A desc ip ion o he knockou mouse model wi h gene alized abla ion o he
gene encoding he COX4I2 subuni iso o m o mi ochond ial complex IV.
46
*
.Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL:
HIF-1 egula es cy och ome oxidase subuni s o op imize
e iciency o espi a ion in hypoxic cells.Cell 2007, 129:
111–122.
HIF1
a
-dependen swi ching o mi ochond ial COX4 subuni iso o m
exp ession in hypoxic cells.
47. A as S, Pak O, Somme N, Finley J R, Hu emann M,
Weissmann N, G ossman LI: Oxygen-dependen exp ession o
cy och ome c oxidase subuni 4-2 gene exp ession is medi-
a ed by ansc ip ion ac o s RBPJ, CXXC5 and CHCHD2.
Nucleic Acids Res 2013, 41:2255–2266.
48. Pajuelo Regue a D, Cuna o a K, V backy M, Pecino a A,
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4 iso o m exchange esul s in modula ion o oxygen a ini y.
Cells 2020, 9.
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Shinzawa-I oh K, Nakashima R, Yaono R, Yoshikawa S: The
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oxidase a 2.8 A.Science 1996, 272:1136–1144.
50. Rakoczy RJ, Schieb el CM, Wya CN: Acu e oxygen-sensing
ia mi ochond ia-gene a ed empe a u e ansien s in a
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51
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.Bishop T, Ra cli e PJ: Gene ic basis o oxygen sensing in he
ca o id body: HIF2alpha and an iso o m swi ch in cy o-
ch ome c oxidase subuni 4.Sci Signal 2020, 13.
An au ho i a i e discussion o da a epo ed in e e ence 21 wi hin he
b oade con ex o HIF2
a
-dependen egula ion o he de elopmen and
unc ion o he ca o id body (CB) and o he ca echolamine gic issues.
The discussion emphasizes he c i ical ole o HIF2
a
in egula ing he
exp ession o CB-speci ic mi ochond ial complex IV subuni iso o ms
essen ial o acu e oxygen sensing in he CB.
52. Dunham-Sna y KJ, Wu D, Po us F, Sykes EA, Mewbu n JD,
Cha les RL, Ea on P, Sul anian RA, A che SL: Ndu s2, a co e
subuni o mi ochond ial complex I, is essen ial o acu e
oxygen-sensing and hypoxic pulmona y asocons ic ion.
Ci c Res 2019, 124:1727–1746.
53
*
.Somme N, Hu emann M, Pak O, Scheibe S, Knoepp F,
Sinkle C, Malczyk M, Gie ha d M, Es andia y A, K au S, e al.:
Mi ochond ial complex IV subuni 4 iso o m 2 is essen ial o
acu e pulmona y oxygen sensing.Ci c Res 2017, 121:
424–438.
This pape desc ibes how he abla ion o he gene encoding he
mi ochond ial complex IV subuni iso o m COX4I2 abolished pulmo-
na y hypoxic asocons ic ion.
54
**
.Mo eno-Dominguez A, Colinas O, A ias-Mayenco I, Cabeza JM,
Lopez-Ogaya JL, Chandel NS, Weissmann N, Somme N,
Pascual A, Lopez-Ba neo J: Hi 1alpha-dependen mi ochon-
d ial acu e O
2
sensing and signaling o myocy e Ca
2+
chan-
nels media e a e ial hypoxic asodila ion.Na Commun 2024,
15:6649.
A de ailed desc ip ion o he mechanism unde lying inhibi ion o L- ype
calcium channel ac i i y in sys emic a e ial smoo h muscle by acu e
hypoxia. The hypoxic signaling pa hway desc ibed he e is essen ially
simila o he mi ochond ial- o-memb ane signaling model p oposed o
ca o id body glomus cells.
8In e ocep ion 2025
Cu en Opinion in Neu obiology 2025, 92:103022 www.sciencedi ec .com
