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How naked mole-rats defy lack of oxygen

An African rodent survives suffocating conditions by switching to a unique type of metabolism based on fructose

Max Delbrück Center for Molecular Medicine in the Helmholtz Association

When oxygen runs low in their underground burrows, naked mole rats have a unique method of survival. Their metabolism switches from a glucose-based system, which depends on oxygen, to one that makes use of fructose. For a while this suffices to protect sensitive organs such as the heart and brain. Scientists of the Max Delbrück Center of Molecular Medicine now explain this unique survival strategy in the current issue of the journal Science.

As most naked mole-rats scurry off to work, some continue to lie on their backs for a while in the sleeping chamber. It's not laziness that keeps these animals from fulfilling their duties in the eusocial community structure of the mole-rats - it's ventilation. 100 naked mole-rats may sleep together in a mound, and last night they were stuck in the middle. „The air can get very stuffy in these underground burrows," says Professor Gary Lewin, a researcher at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). Oxygen levels can drop to conditions that would be life-threatening for other species.

Humans need an atmosphere of at least ten percent oxygen to survive; at lower levels the body cannot generate enough energy for vital cell functions. East African naked mole-rats, however, don't mind atmospheres with much less oxygen for hours on end. They can even survive 18 minutes of total oxygen deprivation by falling into a kind of suspended animation. When this happens, their heart rate drops from 200 to about 50 beats per minute. As soon as they get a sniff of oxygen, they start stirring again as if nothing ever happened. There is no lasting damage.

Unusual sugars found in blood

How naked mole-rats endure these extreme conditions has been a mystery. Now a solution has been found by an international research team headed by Gary Lewin and Thomas Park of the University of Illinois in Chicago. Naked mole-rats have a unique back-up system to carry out metabolism without oxygen. When the oxygen levels are too low to process glucose, a normal source of energy, the animals switch to metabolizing fructose. This supplies energy to cells in vital organs that are highly sensitive to reduced oxygen levels.

A first step was to analyze samples of blood and tissue taken from animals at different times under varying conditions. Dr. Stefan Kempa, who heads the MDC's Metabolomics Unit, measured levels of 86 different metabolites. "There was nothing different in the use of the usual energy source - glucose - between naked mole rats and mice when there was no oxygen around." says Jane Reznick, a lead author on the study from Lewin's team. "But we were quite surprised to find high levels of two unusual sugars - fructose and especially sucrose - in the blood of oxygen-deprived naked mole-rats. These sugars are mainly known for causing metabolic syndrome and sucrose is only made by plants."

Fructose as an alternative energy source

Many mammals can draw on fructose as an energy source - but only in very specific tissues. It can only be used if two components are present. First, there must be a transporter molecule called GLUT5, which draws it from the blood into cells. In most mammals GLUT5 is only present in the liver and kidney. But Reznick found it throughout the mole-rat's body. The second component is an enzyme called KHK, which alters fructose so that it can be fed into an energy-providing pathway called glycolysis whilst at the same time dodging a highly regulated step of glycolysis that is blocked when oxygen levels are low. The mole-rats also had plenty of KHK throughout their bodies. The lack of these two components in the brain and heart of humans and other mammals jams up glycolysis when they are deprived of oxygen. No energy can therefore be provided to power these tissues and the organs quickly fail.

The researchers hypothesized that the survival of the naked mole-rat was due to a metabolic switch from glucose to fructose. This maintained the animal's energy supply and prevented damage when oxygen went missing. They tested the assumption by supplying brains and hearts of naked mole-rats and mice with a solution containing fructose as its sole sugar. The organs of the naked mole rats performed much better than those of mice. Even after one hour, synapses continued to transmit signals. Prof. Michael Gotthardt of the MDC, a specialist in cardiovascular research, demonstrated that the naked mole-rat's heart could perform just as well with fructose as with glucose.

A way to save cells in the heart and the brain?

"Our work is the first evidence that a mammal switches to fructose as a fuel," Lewin says. He is curious whether human cells could also be pushed to switch pathways. "Patients who suffer an infarction or stroke experience irreparable damage after just a few minutes of oxygen deprivation," he says. Since mouse and naked mole-rat are 94% identical on the genetic level: "Theoretically, very few changes might be needed to adopt this unusual metabolism."

In nature, the principle has already proven its value. Naked mole-rats can dig tunnel systems spanning up to 20 kilometers through the East African semi-desert. Before they finally reach the roots and storage tubers of desert plants, the diggers may come to a point of absolute exhaustion and have no oxygen left, says Lewin. If this is a mere interruption the animals can still harvest the roots and carry them back to the colony, for the benefit of all.

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Thomas J. Park, Jane Reznick et al. (2017): „Fructose driven glycolysis supports anoxia resistance in the naked mole-rat." Science.

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