Metabolic Connection of Inflammatory Pain: Pivotal Role of a Pyruvate Dehydrogenase Kinase-Pyruvate Dehydrogenase-Lactic Acid Axis.

Abstract

Pyruvate dehydrogenase kinases (PDK1-4) are mitochondrial metabolic regulators that serve as decision makers via modulation of pyruvate dehydrogenase (PDH) activity to convert pyruvate either aerobically to acetyl-CoA or anaerobically to lactate. Metabolic dysregulation and inflammatory processes are two sides of the same coin in several pathophysiological conditions. The lactic acid surge associated with the metabolic shift has been implicated in diverse painful states. In this study, we investigated the role of PDK-PDH-lactic acid axis in the pathogenesis of chronic inflammatory pain. Deficiency of Pdk2 and/or Pdk4 in mice attenuated complete Freund's adjuvant (CFA)-induced pain hypersensitivities. Likewise, Pdk2/4 deficiency attenuated the localized lactic acid surge along with hallmarks of peripheral and central inflammation following intraplantar administration of CFA. In vitro studies supported the role of PDK2/4 as promoters of classical proinflammatory activation of macrophages. Moreover, the pharmacological inhibition of PDKs or lactic acid production diminished CFA-induced inflammation and pain hypersensitivities. Thus, a PDK-PDH-lactic acid axis seems to mediate inflammation-driven chronic pain, establishing a connection between metabolism and inflammatory pain.

SIGNIFICANCE STATEMENT:

The mitochondrial pyruvate dehydrogenase (PDH) kinases (PDKs) and their substrate PDH orchestrate the conversion of pyruvate either aerobically to acetyl-CoA or anaerobically to lactate. Lactate, the predominant end product of glycolysis, has recently been identified as a signaling molecule for neuron-glia interactions and neuronal plasticity. Pathological metabolic shift and subsequent lactic acid production are thought to play an important role in diverse painful states; however, their contribution to inflammation-driven pain is still to be comprehended. Here, we report that the PDK-PDH-lactic acid axis constitutes a key component of inflammatory pain pathogenesis. Our findings establish an unanticipated link between metabolism and inflammatory pain. This study unlocks a previously ill-explored research avenue for the metabolic control of inflammatory pain pathogenesis.

• Authors: Mithilesh Kumar Jha, Gyun Jee Song, Maan Gee Lee, Nam Ho Jeoung, Younghoon Go, Robert A Harris, Dong Ho Park, Hyun Kook, In-Kyu Lee, Kyoungho Suk
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 35 Issue 42 Pg. 14353-69 (Oct 21 2015) ISSN: 1529-2401 [Electronic] United States
• PMID: 26490872 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 the authors 0270-6474/15/3514354-17$15.00/0.

Chemical References

• Pdk1 protein, mouse
• Pdk2 protein, mouse
• Pdk4 protein, mouse
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Pyruvate Dehydrogenase Complex
• Lactic Acid
• Protein Serine-Threonine Kinases

Topics

• Animals
• Cells, Cultured
• Disease Models, Animal
• Edema (etiology, pathology)
• Gene Expression Regulation (physiology)
• Hyperalgesia (physiopathology)
• Inflammation (complications, congenital)
• Lactic Acid (metabolism)
• Macrophages (pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neural Conduction (genetics)
• Pain (etiology, metabolism)
• Pain Measurement
• Pain Threshold (physiology)
• Protein Serine-Threonine Kinases (deficiency, genetics)
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Pyruvate Dehydrogenase Complex (metabolism)
• Time Factors