title: Metabolic reprogramming by the pyruvate dehydrogenase kinase-lactic acid axis: Linking metabolism and diverse neuropathophysiologies.
abstract: Emerging evidence indicates that 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.
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, BK21 PLUS KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea; Department of Neurology, Division of Neuromuscular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Mithilesh Kumar
authors.initials: MK
authors.lastname: Jha
authors.affiliation: Department of Internal Medicine, Division of Endocrinology and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, BK21 PLUS KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea. Electronic address: ksuk@knu.ac.kr.
authors.forename: Kyoungho
authors.initials: K
authors.lastname: Suk
mesh_terms: D019344:Lactic Acid / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019344:Lactic Acid; D017346:Protein Serine-Threonine Kinases
keywords: Biobehavioral response; Glia; Lactate receptor; Lactate transporter; Lactic acid; Metabolism; Mitochondria; Neurodegeneration; Neuroinflammation; Neuron; Neuropathophysiology; Pain; Pyruvate dehydrogenase kinase