Figure 8.

Schematic diagram summarizing finding of this study. (1) Glucose is imported into cells by the glucose transporter (Glut) and converted to glucose-6p by hexokinase 1 (HK1). (2) Glycolysis eventually generates 2 pyruvate, 2 NADH (NAD+ + H) and 2 ATP molecules. (3) Pyruvate is imported into the mitochondria and converted to acetyl-CoA by pyruvate dehydrogenase (PDH). Acetyl-CoA enters the Krebs cycle where further oxidation can generate around 30 ATP molecules. The rate of PDH enzymatic reaction is attenuated via phosphorylation of PDH by pyruvate dehydrogenase kinase (PDHK). (4) Pyruvate that is not oxidized is converted to lactate by lactate dehydrogenase (LDH), regenerating NAD+. (5) Lactate and a proton are extruded to the extracellular space via monocarboxylate transporter (MCT), which can lead to the activation of a variety of ion channels and receptors that are expressed in different combinations on sensory neurons. Crucially, these targets are known to sensitize primary afferents. In this study, bortezomib treatment increased the expression of PDHK1 in DRGs, resulting in increased phosphorylation of PDH which attenuates pyruvate oxidation. Moreover, bortezomib enhanced the expression of LDHA. Blockade of LDHA or PDHK1 alleviate pain, normalize pyruvate oxidation, and abrogate extracellular acidification.