Effects of Pyruvate Kinase M2 (PKM2) Gene Deletion on Astrocyte-Specific Glycolysis and Global Cerebral Ischemia-Induced Neuronal Death

• Type of Material: Article
• Authors: Beom-Seok Kang, Hallym University; Bo Youg Choi, Hallym University; A-Ra Kho, Johns Hopkins University; Song-Hee Lee, Hallym University; Dae-Ki Hong, Emory University; Min-Kyu Park, Hallym University; Si-Hyun Lee, Hallym University; Chang-Juhn Lee, Hallym University; Hyeun-Wook Yang, Hallym University; Seo-Young Woo, Hallym University; Se-Wan Park, Hallym University; Dong-Yeon Kim, Hallym University; Jae-Bong Park, College of Medicine, Chuncheon 24252, Republic of Korea; Won-Suk Chung, Korea Advanced Institute of Science and Technology; Sang-Won Suh, Hallym University
• Language: English
• Date: 2023-02-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2023 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/antiox12020491
• Title of Journal or Parent Work: ANTIOXIDANTS
• Volume: 12
• Issue: 2
• Grant/Funding Information: This research was supported by funding from the National Research Foundation of Korea (NRF) (NRF-2020R1A2C2008480 to S.W.S.) and by the Korea Health Technology R & D Project through the Korea Health Industry Development Institute (KHIDI) and the Korea Dementia Research Center (KDRC), funded by the Ministry of Health and Welfare and Ministry of Science and ICT, Republic of Korea (grant number: HU20C0206), awarded to S.W.S.
• Keywords: Biochemistry & Molecular Biology; Pharmacology & Pharmacy; pyruvate kinase M2; TRAUMATIC BRAIN-INJURY; global cerebral ischemia; NEUROENERGETICS; Life Sciences & Biomedicine; Food Science & Technology; Chemistry, Medicinal; LACTATE METABOLISM; DEPRIVATION; astrocyte-neuron lactate shuttle; THERAPY; MONOCARBOXYLATE TRANSPORTERS; neuronal death; Science & Technology; GLUCOSE; sodium l-lactate
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Ischemic stroke is caused by insufficient blood flow to the brain. Astrocytes have a role in bidirectionally converting pyruvate, generated via glycolysis, into lactate and then supplying it to neurons through astrocyte–neuron lactate shuttle (ANLS). Pyruvate kinase M2 (PKM2) is an enzyme that dephosphorylates phosphoenolpyruvate to pyruvate during glycolysis in astrocytes. We hypothesized that a reduction in lactate supply in astrocyte PKM2 gene deletion exacerbates neuronal death. Mice harboring a PKM2 gene deletion were established by administering tamoxifen to Aldh1l1-CreERT2; PKM2f/f mice. Upon development of global cerebral ischemia, mice were immediately injected with sodium l-lactate (250 mg/kg, i.p.). To verify our hypothesis, we compared oxidative damage, microtubule disruption, ANLS disruption, and neuronal death between the gene deletion and control subjects. We observed that PKM2 gene deletion increases the degree of neuronal damage and impairment of lactate metabolism in the hippocampal region after GCI. The lactate administration groups showed significantly reduced neuronal death and increases in neuron survival and cognitive function. We found that lactate supply via the ANLS in astrocytes plays a crucial role in maintaining energy metabolism in neurons. Lactate administration may have potential as a therapeutic tool to prevent neuronal damage following ischemic stroke.