Pyruvate dehydrogenase beta subunit (Pdhb) promotes peripheral axon regeneration by regulating energy supply and gene expression

Key metabolic enzymes not only regulate Glucose, lipid, amino acid metabolism to serve the cellular energy needs, but also modulate noncanonical or nonmetabolic signaling pathway such as gene expression, cell-cycle progression, DNA repair, apoptosis and cell proliferation in regulating the pathologic progression of disease. However, the role of glycometabolism in peripheral nerve axon regeneration is little known. In this study, we investigated the expression of Pyruvate dehydrogenase E1(PDH), a key enzyme linking glycolysis and the tricarboxylic acid (TCA) cycle, with qRT-PCR and found that pyruvate dehydrogenase beta subunit (Pdhb) is up-regulated at the early stage during peripheral nerve injury. The knockdown of Pdhb inhibits neurite outgrowth of primary DRG neurons in vitro and restrains axon regeneration of sciatic nerve after crush injury. Pdhb over-expression promoting axonal regeneration is reversed by knockdown of Monocarboxylate transporter 2(Mct2), a transporter involved in the transport and metabolism of lactate, indicating Pdhb promoting axon regeneration depends on lactate for energy supply. Given the nucleus-localization of Pdhb, further analysis revealed that Pdhb enhances the acetylation of H3K9 and affecting the expression of genes involved in arachidonic acid metabolism and Ras signaling pathway, such as Rsa-14-44 and Pla2g4a, thereby promoting axon regeneration. Collectively, our data indicates that Pdhb is a positive dual modulator of energy generation and gene expression in regulating peripheral axon regeneration.

Automated summary

Key metabolic enzymes regulate glucose, lipid, and amino acid metabolism for cellular energy needs and also play a role in nonmetabolic signaling pathways. The role of glycometabolism in peripheral nerve axon regeneration is not well understood. This study found that the up-regulation of Pyruvate dehydrogenase beta subunit (Pdhb), a key enzyme, at the early stage of peripheral nerve injury promotes axon regeneration. Pdhb relies on lactate for energy supply and affects gene expression through histone acetylation, thereby enhancing axon regeneration.