Mitochondrial stress causes neuronal dysfunction via an ATF4-dependent increase in L-2-hydroxyglutarate.

Rachel J Hunt,Joseph M Bateman,Gregory S McElroy,Ramya Ranganathan,Lucy Granat,Navdeep S Chandel

doi:10.1083/jcb.201904148

Rachel J Hunt, Joseph M Bateman + Show 4 more

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https://doi.org/10.1083/jcb.201904148

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Abstract

Mitochondrial stress contributes to a range of neurological diseases. Mitonuclear signaling pathways triggered by mitochondrial stress remodel cellular physiology and metabolism. How these signaling mechanisms contribute to neuronal dysfunction and disease is poorly understood. We find that mitochondrial stress in neurons activates the transcription factor ATF4 as part of the endoplasmic reticulum unfolded protein response (UPR) in Drosophila We show that ATF4 activation reprograms nuclear gene expression and contributes to neuronal dysfunction. Mitochondrial stress causes an ATF4-dependent increase in the level of the metabolite L-2-hydroxyglutarate (L-2-HG) in the Drosophila brain. Reducing L-2-HG levels directly, by overexpressing L-2-HG dehydrogenase, improves neurological function. Modulation of L-2-HG levels by mitochondrial stress signaling therefore regulates neuronal function.

Highlights

Mitochondria play key roles in cellular metabolism including synthesis of ATP, amino acids, reactive oxygen species (ROS), nucleotides, heme, and cholesterol (Spinelli and Haigis, 2018)
TFAM is an HMG box DNA binding protein that binds to the mitochondrial DNA light strand promotor in a complex with the mitochondrial RNA polymerase and TFB2M (Hallberg and Larsson, 2011; Stros et al, 2007)
activating transcription factor 4 (ATF4) is activated by a variety of different mitochondrial stresses in mammalian cultured cells and in vivo (Celardo et al, stress in neurons reprograms metabolism and nuclear gene 2017; Quirós et al, 2017), and persistent activation can be detexpression, potentially regulating neuronal function (Hunt rimental (Khan et al, 2017)

Summary

Introduction

Mitochondria play key roles in cellular metabolism including synthesis of ATP, amino acids, reactive oxygen species (ROS), nucleotides, heme, and cholesterol (Spinelli and Haigis, 2018). Mitochondrial stress–induced activating transcription factor 4 (ATF4) causes neuronal dysfunction To investigate how mitochondrial stress affects the nervous system, we used inducible overexpression of the mitochondrial transcription factor TFAM in Drosophila melanogaster. Consistent with other mitochondrial stress models, TFAM overexpression in neurons causes activation of ATF4 expression in both the larval and adult CNS (Fig. 1, A–D; and Fig. S1, B and C).

Results

Conclusion