mys and Chrysemys) and Eurasian cyprinid
fishes (genus Carassius), such as the cru-
cian carp and the goldfish, which overwin-
ter in the anoxic waters of ice-covered lakes
and ponds (4). These facultative anaerobes
dramatically depress their metabolism and
body temperature, enabling them to survive
on anaerobic fuel stores (glycogen) in a state
of suspended animation or drastically re-
duced activity. No endothermic vertebrates
come close to matching these extreme levels
of anoxia tolerance.
Naked mole-rats (Heterocephalus glaber)
cope with an atmosphere of extremely low
oxygen and high carbon dioxide in their
subterranean burrow systems (see the
photo). Because every aspect of naked mole-rat biology seems to be unusual and bizarre
in some way, it is perhaps not surprising
that they have evolved a particular means
of tolerating low oxygen conditions. Park et
al. observed that naked mole-rats can tolerate an atmosphere of 5% oxygen for 5 hours
without undue stress, whereas mice (Mus
musculus) died of asphyxiation in <15 min.
Under complete anoxia (0% oxygen), mice
and naked mole-rats both quickly lost consciousness. However, whereas mice quickly
passed the point of no return and could not
be resuscitated even when reexposed to ambient air (21% oxygen) within a minute of
the initial anoxia exposure, the naked mole-rats fully recovered from 18 min of complete
anoxia. This may not seem like much when
compared to turtles or crucian carp, but it is
astounding by mammalian standards.
How do naked mole-rats manage to survive for so long under complete anoxia? Like
fishes and turtles living under the ice in
anoxic ponds, the naked mole-rats dramatically reduce energy turnover to safeguard
ATP in the brain and other vital organs.
This metabolic suppression is critically im-
portant because anaerobic pathways are far
less efficient than oxidative phosphoryla-
tion for producing ATP. Unlike fishes and
turtles, however, naked mole-rats do not
maintain large glycogen stores as fuel for
prolonged anaerobic metabolism. A clue as
to what might be going on was provided by
metabolomic profiles of tissues from anoxic
naked mole-rats, which revealed extraor-
dinarily high concentrations of the sugar
fructose. Using stable isotopes, Park et al.
confirmed that naked mole-rats substitute
fructose for glucose as a fuel for anaerobic
metabolism in the brain and heart.
What is the advantage of using fructose
to fuel the anaerobic metabolism of vital
organs? A switch to fructose has the advantage of bypassing a key regulatory step that
limits glycolytic flux. Glucose metabolism is
tightly regulated by phosphofructokinase, a
flux-controlling step that is subject to feedback inhibition by ATP, hydrogen ions, and
citrate. By entering the pathway downstream
of phosphofructokinase, fructose metabolism
can continue under conditions when glycolysis would normally grind to a halt. Like a
cab driver taking a back-road detour around
stopped traffic, this rewiring of metabolism
permits continued flux through glycolysis
independent of the energy status of the cell.
This metabolic innovation required naked
mole-rats to recruit appropriate fructose
transporters and enzymes for expression in
the brain and heart, as they are normally only
expressed in the kidney.
A serious problem with the acceleration
of anaerobic pathways for ATP production
is the associated production of lactate as
an end product. Anoxia-tolerant fishes and
turtles have evolved solutions to this prob-
lem (4). In anoxia, goldfish and carp export
metabolically produced lactate to skeletal
muscle where it is converted to ethanol,
which then diffuses from the gills into the
water. Anoxia-tolerant turtles lack the abil-
ity to produce alternative anaerobic end
products, so they instead evolved a distinct
means of buffering excess lactate and hy-
drogen ions in the blood by releasing cal-
cium carbonate from their shells. Neither of
these exotic mechanisms would be available
to mammals, so it will be interesting to find
out how the naked mole-rats have evolved
their own solution to the problem of lactate
clearance. One possibility is that their abil-
ity to maintain cardiac function in anoxia
facilitates the circulatory clearance of lac-
tate from active tissues. Such possibilities
highlight the value of having a mammalian
model for studying anoxia tolerance.
Glycolysis is an ancient metabolic
pathway and is highly conserved among
vertebrates, so it is surprising that an
evolutionary modification of pathway circuitry has contributed to the remarkable
physiological capacities of naked mole-rats. The adaptations of these enigmatic
mammals also have potential biomedical
relevance, as insights into their previously
unknown metabolic capacities and protective mechanisms may help guide the
design of strategies to mitigate anoxic tissue damage caused by ischemic heart disease or stroke, conditions that are leading
causes of death worldwide (8). j
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The naked mole-rat survives anoxia by switching to fructose-based anaerobic metabolism.