Glutathione S-Transferase Regulates Mitochondrial Populations in Axons through Increased Glutathione Oxidation

Gaynor A. Smith, Tzu Huai Lin, Amy E. Sheehan, Wynand Van der Goes van Naters, Lukas J. Neukomm, Hillary K. Graves, Dana M. Bis-Brewer, Stephan Züchner, Marc Freeman

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)52-65.e6
JournalNeuron
Volume103
Issue number1
DOIs
StatePublished - Jul 3 2019

Fingerprint

Glutathione Disulfide
Glutathione Transferase
Mitochondrial Dynamics
Glutathione
Axons
Thioredoxin Reductase 1
Mitochondrial Degradation
Population
Peroxiredoxins
Neurons
Metabolome
Neurodegenerative Diseases
Drosophila
Oxidation-Reduction
Mitochondria

Keywords

  • axons
  • Drosophila
  • Gfzf
  • glutathione
  • glutathione S-transferases
  • marf
  • mitochondria
  • mitofusin
  • neurons
  • redox

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Smith, G. A., Lin, T. H., Sheehan, A. E., Van der Goes van Naters, W., Neukomm, L. J., Graves, H. K., ... Freeman, M. (2019). Glutathione S-Transferase Regulates Mitochondrial Populations in Axons through Increased Glutathione Oxidation. Neuron, 103(1), 52-65.e6. https://doi.org/10.1016/j.neuron.2019.04.017

Glutathione S-Transferase Regulates Mitochondrial Populations in Axons through Increased Glutathione Oxidation. / Smith, Gaynor A.; Lin, Tzu Huai; Sheehan, Amy E.; Van der Goes van Naters, Wynand; Neukomm, Lukas J.; Graves, Hillary K.; Bis-Brewer, Dana M.; Züchner, Stephan; Freeman, Marc.

In: Neuron, Vol. 103, No. 1, 03.07.2019, p. 52-65.e6.

Research output: Contribution to journalArticle

Smith, GA, Lin, TH, Sheehan, AE, Van der Goes van Naters, W, Neukomm, LJ, Graves, HK, Bis-Brewer, DM, Züchner, S & Freeman, M 2019, 'Glutathione S-Transferase Regulates Mitochondrial Populations in Axons through Increased Glutathione Oxidation', Neuron, vol. 103, no. 1, pp. 52-65.e6. https://doi.org/10.1016/j.neuron.2019.04.017
Smith GA, Lin TH, Sheehan AE, Van der Goes van Naters W, Neukomm LJ, Graves HK et al. Glutathione S-Transferase Regulates Mitochondrial Populations in Axons through Increased Glutathione Oxidation. Neuron. 2019 Jul 3;103(1):52-65.e6. https://doi.org/10.1016/j.neuron.2019.04.017
Smith, Gaynor A. ; Lin, Tzu Huai ; Sheehan, Amy E. ; Van der Goes van Naters, Wynand ; Neukomm, Lukas J. ; Graves, Hillary K. ; Bis-Brewer, Dana M. ; Züchner, Stephan ; Freeman, Marc. / Glutathione S-Transferase Regulates Mitochondrial Populations in Axons through Increased Glutathione Oxidation. In: Neuron. 2019 ; Vol. 103, No. 1. pp. 52-65.e6.
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