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Neurosci. Biobehav. Rev., Available online 11 May 2016 | doi:10.1016/j.neubiorev.2016.05.006 Metabolic reprogramming by the pyruvate dehydrogenase kinase–lactic acid axis: Linking metabolism and diverse neuropathophysiologies

Abstract

Mithilesh Kumar Jha^{a, b}, In-Kyu Lee^c, Kyoungho Suk^a

^a Department of Pharmacology, Brain Science and Engineering Institute, BK21 PLUS KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea
^b Department of Neurology, Division of Neuromuscular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
^c Department of Internal Medicine, Division of Endocrinology and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea

Corresponding author : Kyoungho Suk

Abstract
Emerging evidence indicates there is a complex interplay between metabolism and chronic disorders in the nervous system. In particular, the pyruvate dehydrogenase (PDH) kinase (PDK)-lactic acid axis is a critical link that connects metabolic reprogramming and the pathophysiology of neurological disorders. PDKs, via regulation of PDH complex activity, orchestrate the conversion of pyruvate either aerobically to acetyl-CoA, or anaerobically to lactate. The kinases are also involved in neurometabolic dysregulation under pathological conditions. Lactate, an energy substrate for neurons, is also a recently acknowledged signaling molecule involved in neuronal plasticity, neuron-glia interactions, neuroimmune communication, and nociception. More recently, the PDK-lactic acid axis has been recognized to modulate neuronal and glial phenotypes and activities, contributing to the pathophysiologies of diverse neurological disorders. This review covers the recent advances that implicate the PDK-lactic acid axis as a novel linker of metabolism and diverse neuropathophysiologies. We finally explore the possibilities of employing the PDK-lactic acid axis and its downstream mediators as putative future therapeutic strategies aimed at prevention or treatment of neurological disorders.

Keywords : Pyruvate dehydrogenase kinase; Lactic acid; Neuron; Glia; Neuropathophysiology; Biobehavioral response; Lactate transporter; Lactate receptor; Neuroinflammation; Neurodegeneration; Pain; Metabolism; Mitochondria

논문정보

형식Review Paper
게재일2016년 05월 (BRIC 등록일 2016-05-18)
연구진국내(교신)+국외 연구진
분야 의약학 > 신경의학

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