Amyloid-β Triggers the Release of Neuronal Hexokinase 1 from Mitochondria

Leonardo M Saraiva,Antonio Galina,Fernanda G De Felice,William L Klein,Sérgio T Ferreira,Wagner S Da-Silva,Gisele S Seixas Da Silva,Ashley I Bush

doi:10.1371/journal.pone.0015230

Leonardo M Saraiva, Antonio Galina + Show 6 more

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https://doi.org/10.1371/journal.pone.0015230

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Abstract

Brain accumulation of the amyloid-β peptide (Aβ) and oxidative stress underlie neuronal dysfunction and memory loss in Alzheimer's disease (AD). Hexokinase (HK), a key glycolytic enzyme, plays important pro-survival roles, reducing mitochondrial reactive oxygen species (ROS) generation and preventing apoptosis in neurons and other cell types. Brain isozyme HKI is mainly associated with mitochondria and HK release from mitochondria causes a significant decrease in enzyme activity and triggers oxidative damage. We here investigated the relationship between Aβ-induced oxidative stress and HK activity. We found that Aβ triggered HKI detachment from mitochondria decreasing HKI activity in cortical neurons. Aβ oligomers further impair energy metabolism by decreasing neuronal ATP levels. Aβ-induced HKI cellular redistribution was accompanied by excessive ROS generation and neuronal death. 2-deoxyglucose blocked Aβ-induced oxidative stress and neuronal death. Results suggest that Aβ-induced cellular redistribution and inactivation of neuronal HKI play important roles in oxidative stress and neurodegeneration in AD.

Highlights

Hexokinase (HK) catalyzes the first step of glycolysis, i.e., the ATP-dependent phosphorylation of glucose to glucose-6P (G6P), with concomitant generation of ADP
In agreement with the decrease in levels of mitochondrial-bound hexokinase, the activity determined in the mitochondria-enriched fraction from amyloid-b peptide (Ab)-treated neurons was significantly (,40%) lower than the activity measured in mitochondria from vehicle-treated neurons (Fig. 1B)
In order to investigate the effect of Ab on mitochondrial-bound hexokinase I (m-HKI) activity, we have proceeded checking whether Ab directly inhibits HK. m-HKI activity was measured in mitochondria isolated from adult rat brains incubated with Ab

Summary

Introduction

Hexokinase (HK) catalyzes the first step of glycolysis, i.e., the ATP-dependent phosphorylation of glucose to glucose-6P (G6P), with concomitant generation of ADP. HK is generally known as a key glycolytic enzyme, in neurons and other cell types HK activity regulates vital cellular processes, including ATP synthesis and apoptosis [1,2,3]. Release of HK from mitochondria is known to cause a severe decrease in enzyme activity [5,6]. Mitochondrial-bound hexokinase I (m-HKI) activity in neurons has been shown to be neuroprotective, maintaining adequate glutathione levels, inducing neurite outgrowth, and preventing neuronal oxidative damage [6,7,8]. The activity and specific subcellular localization of neuronal m-HKI is of great significance to protect neurons from different insults

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