Mitochondrial Dysfunction in Astrocytes Impairs the Generation of Reactive Astrocytes and Enhances Neuronal Cell Death in the Cortex Upon Photothrombotic Lesion.

Christian Fiebig,D Chichung Lie,Silke Keiner,Iris Schäffner,Ravi Jagasia,Ruth Beckervordersandforth,Birgit Ebert

doi:10.3389/fnmol.2019.00040

Abstract

Mitochondria are key organelles in regulating the metabolic state of a cell. In the brain, mitochondrial oxidative metabolism is the prevailing mechanism for neurons to generate ATP. While it is firmly established that neuronal function is highly dependent on mitochondrial metabolism, it is less well-understood how astrocytes function rely on mitochondria. In this study, we investigate if astrocytes require a functional mitochondrial electron transport chain (ETC) and oxidative phosphorylation (oxPhos) under physiological and injury conditions. By immunohistochemistry we show that astrocytes expressed components of the ETC and oxPhos complexes in vivo. Genetic inhibition of mitochondrial transcription by conditional deletion of mitochondrial transcription factor A (Tfam) led to dysfunctional ETC and oxPhos activity, as indicated by aberrant mitochondrial swelling in astrocytes. Mitochondrial dysfunction did not impair survival of astrocytes, but caused a reactive gliosis in the cortex under physiological conditions. Photochemically initiated thrombosis induced ischemic stroke led to formation of hyperfused mitochondrial networks in reactive astrocytes of the perilesional area. Importantly, mitochondrial dysfunction significantly reduced the generation of new astrocytes and increased neuronal cell death in the perilesional area. These results indicate that astrocytes require a functional ETC and oxPhos machinery for proliferation and neuroprotection under injury conditions.

Highlights

Astrocytes are highly abundant in the brain (Nedergaard et al, 2003) and central to homeostasis of the nervous system by, e.g., regulating glutamate, ion and water homeostasis, synapse formation and modulation, tissue repair, energy storage, and defense against oxidative stress (Volterra and Meldolesi, 2005; Belanger and Magistretti, 2009)
The requirement and function of mitochondrial oxidative metabolism in astrocyte physiology are a matter of ongoing debate
We investigated the in vivo requirement of electron transport chain (ETC)/oxidative phosphorylation (oxPhos) in cortical astrocytes in physiological and injury context

Summary

Introduction

Astrocytes are highly abundant in the brain (Nedergaard et al, 2003) and central to homeostasis of the nervous system by, e.g., regulating glutamate, ion and water homeostasis, synapse formation and modulation, tissue repair, energy storage, and defense against oxidative stress (Volterra and Meldolesi, 2005; Belanger and Magistretti, 2009). Fine astrocytic processes cover synaptic contacts on one side (Iadecola and Nedergaard, 2007; Oberheim et al, 2009), while on the other side, astrocyte end-feet enwrap the brain microvasculature and regulate the vascular tone as well as blood–brain function (Attwell et al, 2010; Zhao et al, 2015) These morphological characteristics and a special regionalized molecular set-up allow astrocytes to sense neuronal activity at the synapse (via receptors for neurotransmitters, cytokines, growths factors, transporters, and ion channels), and react with the appropriate metabolic supply via their end-feet on the blood vessels (via glucose transporters and aquaporin 4), thereby coordinating synaptic needs and metabolic supply. In many neurodegenerative disorders and under injury conditions, the astrocyte’s response to injury and disease becomes increasingly recognized because astrocytes bare the potential to enhance neuronal survival and regeneration (Sofroniew and Vinters, 2010; Barreto et al, 2012)

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