Abrogating mitochondrial ROS in neurons or astrocytes reveals cell-specific impact on mouse behaviour

Carlos Vicente-Gutierrez,Nicolo Bonora,Daniel Jimenez-Blasco,Irene Lopez-Fabuel,Georgina Bates,Michael P Murphy,Angeles Almeida,Juan P Bolaños

doi:10.1016/j.redox.2021.101917

Carlos Vicente-Gutierrez, Nicolo Bonora + Show 6 more

Open Access

https://doi.org/10.1016/j.redox.2021.101917

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Abstract

Cells naturally produce mitochondrial reactive oxygen species (mROS), but the in vivo pathophysiological significance has long remained controversial. Within the brain, astrocyte-derived mROS physiologically regulate behaviour and are produced at one order of magnitude faster than in neurons. However, whether neuronal mROS abundance differentially impacts on behaviour is unknown. To address this, we engineered genetically modified mice to down modulate mROS levels in neurons in vivo. Whilst no alterations in motor coordination were observed by down modulating mROS in neurons under healthy conditions, it prevented the motor discoordination caused by the pro-oxidant neurotoxin, 3-nitropropionic acid (3-NP). In contrast, abrogation of mROS in astrocytes showed no beneficial effect against the 3-NP insult. These data indicate that the impact of modifying mROS production on mouse behaviour critically depends on the specific cell-type where they are generated.

Highlights

The high energy requirement of neurotransmission is sustained by integrating different metabolic programs of the brain cells [1]
In good agreement with these observations, mitochondria are better coupled [5] and produce about one order of magnitude less mitochondrial reactive oxygen spe cies [6] in neurons than in astrocytes. This vast difference in mROS production is accounted for by the assembly configuration of the mitochondrial respiratory chain supercomplexes [7]. This config uration is tight in neurons to ensure a high energy efficiency, which results in a weaker electron flow to oxygen to form mROS by complex I than that observed in astrocytes [6]
To downregulate endogenous mROS abundance in vivo in a cellspecific manner, we used a mitochondrial-tagged catalase inducible mouse model previously generated in our laboratory [8]

Summary

Introduction

The high energy requirement of neurotransmission is sustained by integrating different metabolic programs of the brain cells [1]. Astrocytes, which have direct access to the bloodstream glucose, mostly rely on glycolysis to obtain energy, whereas neurons depend mainly on oxidative phosphorylation [2,3]. In good agreement with these observations, mitochondria are better coupled [5] and produce about one order of magnitude less mitochondrial reactive oxygen spe cies (mROS) [6] in neurons than in astrocytes. This vast difference in mROS production is accounted for by the assembly configuration of the mitochondrial respiratory chain supercomplexes [7]. We aimed to investigate the cellular and behavioural impact of neuronal mROS abundance both under physio logical and pathological circumstances

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