New research finds that birds can use lactate, often thought of as a metabolic waste product, as a cellular fuel that aids in rapid recovery from a harmful state that impairs oxygen delivery. Haemoglobin, the protein that carries oxygen to our tissues, naturally converts to methaemoglobin, which limits the blood's oxygen-carrying capacity. This research shows how bird red blood cells (RBCs) can use lactate to rapidly resurrect blood function, and they can do this better than mammals because they contain mitochondria — the "powerhouses of the cell" — something that mature mammalian RBCs do not possess.
It is widely thought that mammals have lost mitochondria and nuclei from RBCs to increase oxygen delivery. However, birds and other non-mammalian vertebrates retain these organelles. "This raises an important question: what benefits or costs does the loss of mitochondria incur?" says Yi Yang, a PhD student at the University of Auckland, New Zealand.
Birds have incredibly high energetic needs compared to mammals, and their anatomy and physiology have evolved to use oxygen more efficiently. Miss Yang and her team wanted to investigate the role of the mitochondria in how bird RBCs respond to oxidative stress that damages haemoglobin and explore fuels that could be used to fix damaged RBCs. Of several possible metabolites, lactate appeared to help convert methaemoglobin back to haemoglobin.
Classically, lactate has been thought to be a waste product of anaerobic metabolism during high-intensity exercise, but it is increasingly being recognised as an important signalling molecule. Lactate itself can act as an antioxidant, but it also contains energy and can generate NADH, a molecule used in many pathways, including recharging antioxidant systems and restoring haemoglobin function.
This research, presented at the Society for Experimental Biology conference in Florence, Italy, demonstrates how bird RBCs harness lactate to maintain healthy cellular metabolism.
"Our study shows that lactate helps protect avian RBCs' haemoglobin by harnessing mitochondrial metabolism," says Miss Yang. "As mature mammalian RBCs lack mitochondria, they are unable to fully utilise this pathway."
Lactate can be used by lactate dehydrogenase (LDH) to form NADH and pyruvate. NADH can be used to convert harmful methaemoglobin back into useful haemoglobin, but the pyruvate must be removed or the reaction stops. "Birds, however, can oxidise and remove the resulting pyruvate, which helps sustain NADH production and maintain haemoglobin in its functional state," says Miss Yang.
To assess differences in lactate management of bird and mammalian RBCs, Miss Yang and her team measured LDH activities and types in chickens (Gallus gallus domesticus) and rats (Rattus norvegicus) and measured how much oxygen RBCs consumed inside a controlled chamber, to which they added different metabolic fuels such as lactate and glucose. The team then subjected the RBCs to oxidant challenges that promote the conversion of haemoglobin to methaemoglobin.
They found that lactate enabled chicken RBCs to convert the methaemoglobin back to haemoglobin three times faster than the rat RBCs could. Lactate addition increased apparent oxygen consumption in both chicken and rat RBCs, but the response was substantially greater in chicken RBCs. In part, this was because reformation of functional haemoglobin-bound oxygen, and mitochondria began to oxidise pyruvate.
In addition, chicken RBCs express a form of LDH typically expressed in the heart, while rats express a form associated with skeletal muscle. The heart-type LDH works better at turning lactate to pyruvate.
The most surprising finding of this research is that the mitochondria in bird RBCs support the removal of methaemoglobin. "At first glance, retaining mitochondria might seem risky for bird RBCs because mitochondria result in larger cells, which can impact oxygen delivery," says Miss Yang. "However, our findings show that mitochondria aid methaemoglobin reduction by consuming pyruvate."
While work in the 1970s hinted at lactate use by RBCs containing mitochondria, this is the first time that the mitochondrial mechanisms underlying these processes in bird RBCs have been revealed to protect oxygen supplies.
This research opens up the question of which other cells, tissues and animals are also able to use lactate in this way. Miss Yang and her team are now interested in further investigating the roles of lactate and other metabolic products in other vertebrates.
