Boosting the transport of mitochondria (cell energy suppliers) along neuronal axons enhances the ability of mouse nerve cells to repair themselves and regrow after injury or disease, researchers at the National Institute of Neurological Disorders and Stroke report in The Journal of Cell Biology.

Neurons need large amounts of energy to extend their axons long distances through the body. This energy — in the form of adenosine triphosphate (ATP) — is provided by mitochondria.

During development, mitochondria are transported up and down growing axons to generate ATP wherever it is needed. In adults, however, mitochondria become less mobile as mature neurons produce a protein called syntaphilin that anchors the mitochondria in place.

Zu-Hang Sheng and colleagues at the National Institute of Neurological Disorders and Stroke wondered whether this decrease in mitochondrial transport might explain why adult neurons are typically unable to regrow after injury.

They initially found that when mature mouse axons are severed, nearby mitochondria are damaged and become unable to provide sufficient ATP to support injured nerve regeneration. However, when the researchers experimentally removed syntaphilin from the nerve cells (by using a genetically modified mouse), mitochondrial transport was enhanced, allowing the damaged mitochondria to be replaced by healthy mitochondria capable of producing ATP.

The Syntaphilin-deficient mature neurons therefore regained the ability to regrow after injury, just like young neurons.

“Our in vivo and in vitro studies suggest that activating an intrinsic growth program requires the coordinated modulation of mitochondrial transport and recovery of energy deficits. Such combined approaches may represent a valid therapeutic strategy to facilitate regeneration in the central and peripheral nervous systems after injury or disease,” Sheng says.

Abstract of Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits

Although neuronal regeneration is a highly energy-demanding process, axonal mitochondrial transport progressively declines with maturation. Mature neurons typically fail to regenerate after injury, thus raising a fundamental question as to whether mitochondrial transport is necessary to meet enhanced metabolic requirements during regeneration. Here, we reveal that reduced mitochondrial motility and energy deficits in injured axons are intrinsic mechanisms controlling regrowth in mature neurons. Axotomy induces acute mitochondrial depolarization and ATP depletion in injured axons. Thus, mature neuron-associated increases in mitochondria-anchoring protein syntaphilin (SNPH) and decreases in mitochondrial transport cause local energy deficits. Strikingly, enhancing mitochondrial transport via genetic manipulation facilitates regenerative capacity by replenishing healthy mitochondria in injured axons, thereby rescuing energy deficits. An in vivo sciatic nerve crush study further shows that enhanced mitochondrial transport in snph knockout mice accelerates axon regeneration. Understanding deficits in mitochondrial trafficking and energy supply in injured axons of mature neurons benefits development of new strategies to stimulate axon regeneration.