The Impact of Acetyl-CoA and Aspartate Shortages on the N-Acetylaspartate Level in Different Models of Cholinergic Neurons

Marlena Zyśk,Tadeusz Pawełczyk,Anna Michno,Monika Sakowicz-Burkiewicz,Piotr Pikul,Robert Kowalski

doi:10.3390/antiox9060522

Abstract

N-acetylaspartate is produced by neuronal aspartate N-acetyltransferase (NAT8L) from acetyl-CoA and aspartate. In cholinergic neurons, acetyl-CoA is also utilized in the mitochondrial tricarboxylic acid cycle and in acetylcholine production pathways. While aspartate has to be shared with the malate–aspartate shuttle, another mitochondrial machinery together with the tricarboxylic acid cycle supports the electron transport chain turnover. The main goal of this study was to establish the impact of toxic conditions on N-acetylaspartate production. SN56 cholinergic cells were exposed to either Zn2+ overload or Ca2+ homeostasis dysregulation and male adult Wistar rats’ brains were studied after 2 weeks of challenge with streptozotocin-induced hyperglycemia or daily theophylline treatment. Our results allow us to hypothesize that the cholinergic neurons from brain septum prioritized the acetylcholine over N-acetylaspartate production. This report provides the first direct evidence for Zn2+-dependent suppression of N-acetylaspartate synthesis leading to mitochondrial acetyl-CoA and aspartate shortages. Furthermore, Zn2+ is a direct concentration-dependent inhibitor of NAT8L activity, while Zn2+-triggered oxidative stress is unlikely to be significant in such suppression.

Highlights

Aspartate N-acetyltransferase (NAT8L) is a neuronal enzyme producing N-acetylaspartate (NAA)from acetyl-CoA and aspartate (Figure 1A) [1,2,3]
Our previous studies showed a significant impact of Zn2+ -related toxicity on the expression of cholinergic phenotype as well as on the level of N-acetylaspartate (NAA) in SN56 cells [4,10,11,12]
The exact influence of Zn2+ on NAA production has not been established yet, it is known that Zn2+ affects pyruvate dehydrogenase activity leading to acetyl-CoA shortages in SN56 cells [4,10,11,12]

Summary

Introduction

Aspartate N-acetyltransferase (NAT8L) is a neuronal enzyme producing N-acetylaspartate (NAA)from acetyl-CoA and aspartate (Figure 1A) [1,2,3]. In cholinergic neurons, NAA synthesis has to share acetyl-CoA with the tricarboxylic acid cycle and the acetylcholine production pathway, while aspartate is shared with the aspartate—malate shuttle [2,3,4,5]. Both the tricarboxylic acid cycle and the malate–aspartate shuttle are the main participants of the mitochondrial machinery supporting electron transport chain turnover. NAA as well as acetylcholine are produced to fulfill the neuronal functions linked with cell-cell interactions They have to Antioxidants 2020, 9, 522; doi:10.3390/antiox9060522 www.mdpi.com/journal/antioxidants

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