Impairment of Autophagic Flux Promotes Glucose Reperfusion-Induced Neuro2A Cell Death after Glucose Deprivation

PLOS ONE, Dec 2019

Hypoglycemia-induced brain injury is a common and serious complication of intensive insulin therapy experienced by Type 1 diabetic patients. We previously reported that hypoglycemic neuronal death is triggered by glucose reperfusion after hypoglycemia rather than as a simple result of glucose deprivation. However, the precise mechanism of neuronal death initiated by glucose reperfusion is still unclear. Autophagy is a self-degradation process that acts through a lysosome-mediated trafficking pathway to degrade and recycle intracellular components, thereby regulating metabolism and energy production. Recent studies suggest that autophagic and lysosomal dysfunction leads to abnormal protein degradation and deposition that may contribute to neuronal death. Here, we focused on the relationship between autophagy and lysosomal dysfunction in hypoglycemia-induced neuronal death. In neuronal cells, glucose reperfusion after glucose deprivation resulted in inhibition of autophagy, which may promote cell death. This cell death was accompanied with activation of caspase3 and the lysosomal proteases cathepsin B and D, which indicated impairment of autophagic flux. Taken together, these results suggest that interplay of autophagy, caspase3 activation and lysosomal proteases serve as a basis for neuronal death after hypoglycemia. Thus, we provide the molecular mechanism of neuronal death by glucose reperfusion and suggest some clues for therapeutic strategies to prevent hypoglycemia-induced neuronal death.

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Impairment of Autophagic Flux Promotes Glucose Reperfusion-Induced Neuro2A Cell Death after Glucose Deprivation

et al. (2013) Impairment of Autophagic Flux Promotes Glucose Reperfusion-Induced Neuro2A Cell Death after Glucose Deprivation. PLoS ONE 8(10): e76466. doi:10.1371/journal.pone.0076466 Impairment of Autophagic Flux Promotes Glucose Reperfusion-Induced Neuro2A Cell Death after Glucose Deprivation Bong Geom Jang 0 Bo Young Choi 0 Jin Hee Kim 0 Min-Ju Kim 0 Min Sohn 0 Sang Won Suh 0 Chih-Hsin Tang, China Medical University, Taiwan 0 1 Department of Physiology, Hallym University, College of Medicine, Chuncheon, Republic of Korea, 2 Department of Anatomy and Neurobiology, Hallym University, College of Medicine, Chuncheon, Republic of Korea, 3 Inha University, Department of Nursing , Incheon , Republic of Korea Hypoglycemia-induced brain injury is a common and serious complication of intensive insulin therapy experienced by Type 1 diabetic patients. We previously reported that hypoglycemic neuronal death is triggered by glucose reperfusion after hypoglycemia rather than as a simple result of glucose deprivation. However, the precise mechanism of neuronal death initiated by glucose reperfusion is still unclear. Autophagy is a self-degradation process that acts through a lysosomemediated trafficking pathway to degrade and recycle intracellular components, thereby regulating metabolism and energy production. Recent studies suggest that autophagic and lysosomal dysfunction leads to abnormal protein degradation and deposition that may contribute to neuronal death. Here, we focused on the relationship between autophagy and lysosomal dysfunction in hypoglycemia-induced neuronal death. In neuronal cells, glucose reperfusion after glucose deprivation resulted in inhibition of autophagy, which may promote cell death. This cell death was accompanied with activation of caspase3 and the lysosomal proteases cathepsin B and D, which indicated impairment of autophagic flux. Taken together, these results suggest that interplay of autophagy, caspase3 activation and lysosomal proteases serve as a basis for neuronal death after hypoglycemia. Thus, we provide the molecular mechanism of neuronal death by glucose reperfusion and suggest some clues for therapeutic strategies to prevent hypoglycemia-induced neuronal death. - Funding: This work was supported by the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A120202) and by a grant from the Hallym University Specialization Fund (HRF-S-41) to S.W.S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Hypoglycemia, known commonly as low blood glucose or low blood sugar, is a state characterized by an abnormally low level of blood glucose compared with the normal physiologic range. The most common form of hypoglycemia occurs as a complication in diabetic patients who attempt tight control of blood glucose levels with insulin or oral glucose lowering medications [1]. Glucose is a major metabolic fuel for the brain, which cannot synthesize glucose; therefore an insufficient supply of glucose to the brain results in a loss of neurons as well as impairment of function [2]. According to studies using animal models, acute/severe hypoglycemia [blood glucose (BG) , 18 mg/dL; 1 mM/L] induces neuronal damage in the vulnerable neurons of cortex and hippocampus [3]. In particular, this neuronal injury in hippocampus results in a decline in learning and memory [4]. Thus, understanding of the mechanisms of neuronal death accompanying hypoglycemia is fundamentally important for the prevention of post-hypoglycemia pathophysiology. Although hypoglycemic brain injury was first demonstrated by Auer three decades ago[3], little is known about the precise molecular mechanism of neuronal death by hypoglycemia. We previously suggested that hypoglycemia-induced neuronal death is triggered by glucose reperfusion after acute/severe hypoglycemia rather than by hypoglycemia per se [5]. Accumulating evidence has demonstrated that glucose reperfusion injury is a multi-factorial process, ultimately culminating in hypoglycemiainduced neuronal death. For example, glucose reperfusion after hypoglycemia triggers activation of NADPH oxidase, which causes reactive oxygen species (ROS) production, subsequent activation of poly(ADP-ribose) polymerase, and resultant neuronal death [5 7]. Also, mitochondrial permeability transition and calpain activation have been shown to accompany hypoglycemia-induced neuronal death [8]. However, the precise molecular mechanism(s) that lead(s) to neuronal cell death by glucose reperfusion after hypoglycemia is still unclear. Autophagy is a conserved catabolic process involving the degradation of intracellular macromolecules and organelles in mammalian cells via the lysosomal system. During autophagy, the cellular components are sequestered into double-membrane vesicles (autophagosomes), w (...truncated)


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Bong Geom Jang, Bo Young Choi, Jin Hee Kim, Min-Ju Kim, Min Sohn, Sang Won Suh. Impairment of Autophagic Flux Promotes Glucose Reperfusion-Induced Neuro2A Cell Death after Glucose Deprivation, PLOS ONE, 2013, Volume 8, Issue 10, DOI: 10.1371/journal.pone.0076466