Glycolytic System in Axons Supplement Decreased ATP Levels after Axotomy of the Peripheral Nerve

Wallerian Degeneration (WD) occurs in the early stages of numerous neurological disorders, and clarifying WD pathology is crucial for the advancement of neurological therapies. Adenosine triphosphate (ATP) is acknowledged as one of the key pathological substances in WD. The ATP-related pathological pathways that regulate WD have been defined. The elevation of ATP levels in axon contributes to delay WD and protects axons. While, ATP is necessary for the active processes to proceed WD, given that WD is stringently managed by auto-destruction programs. However, little is known about the bioenergetics during WD. In this study, we made sciatic nerve transection models for GO-ATeam2 knock-in rats and mice. We presented the spatiotemporal ATP distribution in the injured axons with in vivo ATP imaging systems, and investigated the metabolic source of ATP in the distal nerve stump. A gradual decrease in ATP levels was observed before the progression of WD. In addition, the glycolytic system and monocarboxylate transporters (MCTs) were activated in Schwann cells following axotomy. Interestingly, in axons, we found the activation of glycolytic system and the inactivation of the tricarboxylic acid (TCA) cycle. Glycolytic inhibitors, 2-deoxyglucose (2-DG) and MCT inhibitors, a-cyano-4-hydroxycinnamic acid (4-CIN) decreased ATP and enhanced WD progression, whereas mitochondrial pyruvate carrier (MPC) inhibitors (MSDC-0160) did not change. Finally, ethyl pyruvate (EP) increased ATP levels and delayed WD. Together, our findings suggest that glycolytic system, both in Schwann cells and axons, is the main source of maintaining ATP levels in the distal nerve stump.Significance StatementWallerian degeneration after axotomy is associated with decreasing ATP levels. To maintain ATP levels, Schwann cells activate the glycolytic systems and produce monocarboxylate, which is transported to axons via MCTs. Axons also activate the glycolysis system to obtain ATP, and inactivate TCA cycle due to mitochondrial degeneration. The glycolysis with MCT-induced monocarboxylate transport contributes to the ATP production in degenerative axons.

ATP; Wallerian degeneration; glycolytic system; in vivo imaging; mitochondria.