Jha Mithilesh Kumar, Song Gyun Jee, Lee Maan Gee, Jeoung Nam Ho, Go Younghoon, Harris Robert A, Park Dong Ho, Kook Hyun, Lee In-Kyu, Suk Kyoungho
Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, 700-422, Republic of Korea.
Department of Pharmaceutical Science and Technology, Catholic University of Daegu, Gyeongsan, Republic of Korea.
J Neurosci. 2015 Oct 21;35(42):14353-69. doi: 10.1523/JNEUROSCI.1910-15.2015.
UNLABELLED: 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.
未标记：丙酮酸脱氢酶激酶（PDK1 - 4）是线粒体代谢调节因子，通过调节丙酮酸脱氢酶（PDH）的活性，决定丙酮酸是通过有氧途径转化为乙酰辅酶A，还是通过无氧途径转化为乳酸，从而起到决策者的作用。在几种病理生理状态下，代谢失调和炎症过程是同一问题的两个方面。与代谢转变相关的乳酸激增与多种疼痛状态有关。在本研究中，我们调查了PDK - PDH - 乳酸轴在慢性炎症性疼痛发病机制中的作用。小鼠中Pdk2和/或Pdk4的缺失减轻了完全弗氏佐剂（CFA）诱导的疼痛超敏反应。同样，Pdk2/4缺失减弱了局部乳酸激增以及足底注射CFA后外周和中枢炎症的特征。体外研究支持PDK2/4作为巨噬细胞经典促炎激活促进因子的作用。此外，PDK或乳酸生成的药理学抑制减轻了CFA诱导的炎症和疼痛超敏反应。因此，PDK - PDH - 乳酸轴似乎介导了炎症驱动的慢性疼痛，建立了代谢与炎症性疼痛之间的联系。 意义声明：线粒体丙酮酸脱氢酶（PDH）激酶（PDKs）及其底物PDH协调丙酮酸通过有氧途径转化为乙酰辅酶A或通过无氧途径转化为乳酸。乳酸是糖酵解的主要终产物，最近已被确定为神经元 - 神经胶质细胞相互作用和神经元可塑性的信号分子。病理性代谢转变和随后的乳酸生成被认为在多种疼痛状态中起重要作用；然而，它们对炎症驱动疼痛的贡献仍有待理解。在此，我们报告PDK - PDH - 乳酸轴构成炎症性疼痛发病机制的关键组成部分。我们的发现建立了代谢与炎症性疼痛之间意想不到的联系。本研究为炎症性疼痛发病机制的代谢控制开启了一条此前未充分探索的研究途径。
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