GRAPHIC: KELLIE HOLOSKI/SCIENCEscience.org SCIENCEBy Sanjeethan C. Bakshand Lydia W. S. FinleyT
he flow of electrons sustains all living
organisms. Metabolic networks har-
ness the chemical energy of nutrients
by capturing high-energy electrons,
which are then deposited onto the mi-
tochondrial electron transport chain
(ETC). Here, a series of protein complexes
couple oxidation-reduction reactions to the
generation of an electrochemical potential
that drives synthesis of adenosine triphos-
phate, a common energy currency. Electron
flow through the ETC is also critical for
myriad other cellular functions, including
biosynthetic and signaling processes ( 1 ). In
metazoans, oxygen enables continual elec-
tron flow by serving as a terminal electron
acceptor. Nevertheless, many cells exist in
oxygen-poor environments while
sustaining ETC-dependent reac-
tions ( 2 ), raising the question of
where electrons go when they
cannot reduce molecular oxy-
gen. On page 1227 of this issue,
Spinelli et al. ( 3 ) identify the
tricarboxylic acid (TCA) cycle
metabolite fumarate as an alter-
native electron acceptor.
At the heart of the ETC is the
electron carrier ubiquinone,
which accepts electrons from
inputs into the ETC, forming
ubiquinol. Ubiquinol oxida-
tion by complex III of the ETC
regenerates the oxidized ubi-
quinone required to enable con-
tinual electron donation into
the ETC. Thus, blocking ubiqui-
none regeneration by ablating
complex III or its downstream
partner, complex IV (which re-
duces molecular oxygen), should
ultimately block any metabolic
pathway that depends on depos-
iting electrons into the ETC ( 4 ).
However, Spinelli et al. found
that genetic ablation of complex
III or IV in human cancer cellsdid not abolish electron flow. This observa-
tion demonstrates that oxygen is not required
for ETC function and suggests the existence
of alternative terminal electron acceptors.
Both hypoxia and ETC inhibition were
associated with increased amounts of suc-
cinate, a TCA cycle intermediate that con-
ventionally deposits electrons to ubiquinone
through complex II of the ETC, thereby form-
ing fumarate. Under basal conditions, most
succinate is generated by oxidative metabo-
lism of substrates in the TCA cycle. Spinelli
et al. demonstrated that during low oxygen
or ETC inhibition, a portion of succinate was
generated from fumarate, suggesting that fu-
marate reduction to succinate may provide a
valve for excess electrons from the ETC. No-
tably, fumarate was not passively capturing
rogue electrons leaking from the ETC; rather,fumarate reduction was catalyzed specifically
by complex II itself (see the figure).
Spinelli et al. demonstrated that the ability
of complex II to operate in reverse and reduce
fumarate required increased concentrations
of ubiquinol relative to ubiquinone. Under
conditions of extremely impaired ubiqui-
none regeneration, the relatively unfavorable
reaction of fumarate reduction by complex
II becomes permissive, siphoning electrons
from the ubiquinol pool on to fumarate. This
is consistent with prior work demonstrating
that either complex I or complex II, each of
which deposits electrons into the ETC, can
reverse directionality and accept electrons
from ubiquinol during conditions of low
oxygen or ETC inhibition (5, 6). By provid-
ing an alternative route for ubiquinol oxi-
dation, reversed complex II activity enables
oxidative metabolic networks to continue to
deposit electrons into the ETC even when
oxygen cannot serve as an electron acceptor.
This work therefore calls into question the
widely held notion that hypoxia will inhibit
pathways that depend on ETC function and
cautions that oxygen consumption does not
always represent ETC activity. Intriguingly,
as stem cells frequently reside within hypoxic
niches ( 7 ), the work by Spinelli et al. raises
the possibility that reverse complex II activ-
ity may support ETC-dependent
cell-fate decisions , for example,
by regulating succinate and nu-
cleotide pools, thereby regulat-
ing gene expression (7–10).
Spinelli et al. find that com-
plex II reversal is not limited
to extreme conditions of low
oxygen or impaired ETC activity.
Carbon tracing strategies in mice
revealed a surprising hetero-
geneity in the degree to which
tissues generate succinate from
fumarate. Some tissues never
demonstrated fumarate reduc-
tion; others reduced fumarate
after physiological challenges
such as exercise or hypoxia.
Other tissues, such as kidney,
liver, and brain showed consti-
tutive production of succinate
from fumarate regardless of
oxygen availability. Although the
mechanisms governing the abil-
ity of tissues to initiate complex
II reversal and fumarate reduc-
tion remain to be elucidated,
these results reveal the intrinsic
diversity of ETC wiring across
mammalian tissues.
What is the benefit of revers-
ing complex II? One possibility
is that this may allow tissues to
cope with “reductive” stress—Cell Biology Program, Memorial Sloan
Kettering Cancer Center, New York, NY, USA.
Email: [email protected]Cyt cCyt cCCCCytCyCyyytyytttcccccCCyCCytCCyCyyyyttttccccCyt c, cytochrome c; DHO, dihydroorotate; DHODH, dihydroorotate dehydrogenase; FADH 2 , flavin adenine di-
nucleotide; NADH, nicotinamide adenine dinucleotide; SDH, succinate dehydrogenase; TCA, tricarboxylic acid.I II III IV4H+ 4H+ 2H+NADH NAD+ FADH 2 FA DTCA cycleInner
membraneIntermembrane
spaceMitochondrial
matrixO 2 H 2 OUbiquinolSDHDHO Orotate PyrimidinesDHODHNormoxiaHypoxiaSuccinate FumarateI II III IV4H+ 4H+ 2H+NADH NAD+TCA cycleDHO Orotate PyrimidinesSuccinateFumarateFA D H 2 FA DO 2 H 2 OSDH
HypoxiaMitochondrial
stressorse–e–e–
e–e–
e–e–METABOLISMShort-circuiting respiration
PERSPECTIVES
Fumarate siphons electrons to keep metabolism running
INSIGHTSElectron flow
Under normoxia, electrons flow through ubiquinol to oxygen as
a terminal electron acceptor. When oxygen reduction is limiting,
electrons accumulate on ubiquinol, leading to reverse electron
flow through SDH, generating succinate from fumarate.1196 3 DECEMBER 2021 • VOL 374 ISSUE 6572