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

• 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
• Journal Title: ANTIOXIDANTS
• Volume: Volume 12, Number 2
• Publisher: MDPI | 2023-02-01
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.3390/antiox12020491
• Subjects: Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; Chemistry, Medicinal; Food Science & Technology; Pharmacology & Pharmacy; global cerebral ischemia; astrocyte-neuron lactate shuttle; pyruvate kinase M2; sodium l-lactate; neuronal death; TRAUMATIC BRAIN-INJURY; MONOCARBOXYLATE TRANSPORTERS; LACTATE METABOLISM; GLUCOSE; NEUROENERGETICS; DEPRIVATION; THERAPY

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.