Improving Mitochondrial Function in Neurons to Boost Nerve Regeneration
Mitochondria are the power plants of the cell, responsible for producing the chemical energy store molecule adenosine triphosphate (ATP) that powers cellular operations. As such, most processes of interest in disease and regeneration have at least some indirect dependency on mitochondrial function. Researchers here note a potential connection between mitochondrial function and the inability of nerves to regrow following injury. They provide evidence for an adjustment to the way in which mitochondria behave in nerve cells, and in the connections between nerve cells called axons, to spur regeneration. This is an interesting approach to regenerative medicine, though clearly at a very early stage of exploration.
The cells of the body use a chemical compound called adenosine triphosphate (ATP) for fuel. Much of this ATP is made by cellular power plants called mitochondria. In spinal cord nerves, mitochondria can be found along the axons. When axons are injured, the nearby mitochondria are often damaged as well, impairing ATP production in injured nerves. "Nerve repair requires a significant amount of energy. Our hypothesis is that damage to mitochondria following injury severely limits the available ATP, and this energy crisis is what prevents the regrowth and repair of injured axons."
Adding to the problem is the fact that, in adult nerves, mitochondria are anchored in place within axons. This forces damaged mitochondria to remain in place while making it difficult to replace them, thus accelerating a local energy crisis in injured axons. One of the leading groups studying mitochondrial transport previously created genetic mice that lack the protein - called Syntaphilin - that tethers mitochondria in axons. In these "knockout mice" the mitochondria are free to move throughout axons.
When the researchers looked in three injury models in the spinal cord and brain, they observed that Syntaphilin knockout mice had significantly more axon regrowth across the injury site compared to control animals. The newly grown axons also made appropriate connections beyond the injury site. When the researchers looked at whether this regrowth led to functional recovery, they saw some promising improvement in fine motor tasks in mouse forelimbs and fingers. This suggested that increasing mitochondrial transport and thus the available energy to the injury site could be key to repairing damaged nerve fibers. To test the energy crisis model further, mice were given creatine, a bioenergetic compound that enhances the formation of ATP. Both control and knockout mice that were fed creatine showed increased axon regrowth following injury compared to mice fed saline instead. More robust nerve regrowth was seen in the knockout mice that got the creatine.