@article{f6012ca3351e470e9f30f629c861c94c,
title = "Glutathione S-Transferase Regulates Mitochondrial Populations in Axons through Increased Glutathione Oxidation",
abstract = "Mitochondria are essential in long axons to provide metabolic support and sustain neuron integrity. A healthy mitochondrial pool is maintained by biogenesis, transport, mitophagy, fission, and fusion, but how these events are regulated in axons is not well defined. Here, we show that the Drosophila glutathione S-transferase (GST) Gfzf prevents mitochondrial hyperfusion in axons. Gfzf loss altered redox balance between glutathione (GSH) and oxidized glutathione (GSSG) and initiated mitochondrial fusion through the coordinated action of Mfn and Opa1. Gfzf functioned epistatically with the thioredoxin peroxidase Jafrac1 and the thioredoxin reductase 1 TrxR-1 to regulate mitochondrial dynamics. Altering GSH:GSSG ratios in mouse primary neurons in vitro also induced hyperfusion. Mitochondrial changes caused deficits in trafficking, the metabolome, and neuronal physiology. Changes in GSH and oxidative state are associated with neurodegenerative diseases like Alzheimer's. Our demonstration that GSTs are key in vivo regulators of axonal mitochondrial length and number provides a potential mechanistic link.",
keywords = "Drosophila, Gfzf, axons, glutathione, glutathione S-transferases, marf, mitochondria, mitofusin, neurons, redox",
author = "Smith, {Gaynor A.} and Lin, {Tzu Huai} and Sheehan, {Amy E.} and {Van der Goes van Naters}, Wynand and Neukomm, {Lukas J.} and Graves, {Hillary K.} and Bis-Brewer, {Dana M.} and Stephan Z{\"u}chner and Freeman, {Marc R.}",
note = "Funding Information: We would like to thank the Imaging core at Oregon Health and Science University and the Bio-Imaging Hub at Cardiff University for their outstanding input to our microscope requirements and the Metabolomics Core at University of California Davis for their analysis and advice. This work was funded by an HHMI Investigator Award (to M.R.F.), the NIH (R21 grant NS098364 to M.R.F. and G.A.S., R01 grant NS075764 to S.Z., and R01 grant NS059991 to M.R.F.), a Charles A. King Trust Postdoctoral Fellowship (to L.J.N.), and the MRC Momentum Award ( MC_PC_16030/1 to G.A.S.). Funding Information: We would like to thank the Imaging core at Oregon Health and Science University and the Bio-Imaging Hub at Cardiff University for their outstanding input to our microscope requirements and the Metabolomics Core at University of California Davis for their analysis and advice. This work was funded by an HHMI Investigator Award (to M.R.F.), the NIH (R21 grant NS098364 to M.R.F. and G.A.S. R01 grant NS075764 to S.Z. and R01 grant NS059991 to M.R.F.), a Charles A. King Trust Postdoctoral Fellowship (to L.J.N.), and the MRC Momentum Award (MC_PC_16030/1 to G.A.S.). G.A.S. T.-H.L. and M.R.F. conceived ideas, wrote the paper, and did experiments; A.E.S. W.V.d.G.v.N. L.J.N. H.K.G. D.M.B.-B. and S.Z. did experiments or contributed unpublished reagents. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = jul,
day = "3",
doi = "10.1016/j.neuron.2019.04.017",
language = "English (US)",
volume = "103",
pages = "52--65.e6",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "1",
}