Structural and functional rescue of chronic metabolically stressed optic nerves through respiration

Mohammad Harun-Or-Rashid, Nate Pappenhagen, Peter G. Palmer, Matthew A. Smith, Victoria Gevorgyan, Gina N. Wilson, Samuel D. Crish, Denise Maureen Inman

Research output: Contribution to journalArticle

Abstract

Axon degeneration can arise from metabolic stress, potentially a result of mitochondrial dysfunction or lack of appropriate substrate input. In this study, we investigated whether the metabolic vulnerability observed during optic neuropathy in the DBA/2J (D2) model of glaucoma is due to dysfunctional mitochondria or impaired substrate delivery to axons, the latter based on our observation of significantly decreased glucose and monocarboxylate transporters in D2 optic nerve (ON), human ON, and mice subjected to acute glaucoma injury. We placed both sexes of D2 mice destined to develop glaucoma and mice of a control strain, the DBA/2J-Gpnmb+, on a ketogenic diet to encourage mitochondrial function. Eight weeks of the diet generated mitochondria, improved energy availability by reversing monocarboxylate transporter decline, reduced glial hypertrophy, protected retinal ganglion cells and their axons from degeneration, and maintained physiological signaling to the brain. A robust antioxidant response also accompanied the response to the diet. These results suggest that energy compromise and subsequent axon degeneration in the D2 is due to low substrate availability secondary to transporter downregulation.

Original languageEnglish
Pages (from-to)5122-5139
Number of pages18
JournalJournal of Neuroscience
Volume38
Issue number22
DOIs
StatePublished - 30 May 2018

Fingerprint

Optic Nerve
Axons
Respiration
Glaucoma
Mitochondria
Ketogenic Diet
Diet
Optic Nerve Diseases
Inbred DBA Mouse
Physiological Stress
Facilitative Glucose Transport Proteins
Retinal Ganglion Cells
Neuroglia
Hypertrophy
Down-Regulation
Antioxidants
Observation
Wounds and Injuries
Brain

Keywords

  • B-hydroxybutyrate
  • Ketogenic diet
  • Neural-glial interaction
  • Optic nerve

Cite this

Harun-Or-Rashid, M., Pappenhagen, N., Palmer, P. G., Smith, M. A., Gevorgyan, V., Wilson, G. N., ... Inman, D. M. (2018). Structural and functional rescue of chronic metabolically stressed optic nerves through respiration. Journal of Neuroscience, 38(22), 5122-5139. https://doi.org/10.1523/JNEUROSCI.3652-17.2018
Harun-Or-Rashid, Mohammad ; Pappenhagen, Nate ; Palmer, Peter G. ; Smith, Matthew A. ; Gevorgyan, Victoria ; Wilson, Gina N. ; Crish, Samuel D. ; Inman, Denise Maureen. / Structural and functional rescue of chronic metabolically stressed optic nerves through respiration. In: Journal of Neuroscience. 2018 ; Vol. 38, No. 22. pp. 5122-5139.
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Harun-Or-Rashid, M, Pappenhagen, N, Palmer, PG, Smith, MA, Gevorgyan, V, Wilson, GN, Crish, SD & Inman, DM 2018, 'Structural and functional rescue of chronic metabolically stressed optic nerves through respiration', Journal of Neuroscience, vol. 38, no. 22, pp. 5122-5139. https://doi.org/10.1523/JNEUROSCI.3652-17.2018

Structural and functional rescue of chronic metabolically stressed optic nerves through respiration. / Harun-Or-Rashid, Mohammad; Pappenhagen, Nate; Palmer, Peter G.; Smith, Matthew A.; Gevorgyan, Victoria; Wilson, Gina N.; Crish, Samuel D.; Inman, Denise Maureen.

In: Journal of Neuroscience, Vol. 38, No. 22, 30.05.2018, p. 5122-5139.

Research output: Contribution to journalArticle

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Harun-Or-Rashid M, Pappenhagen N, Palmer PG, Smith MA, Gevorgyan V, Wilson GN et al. Structural and functional rescue of chronic metabolically stressed optic nerves through respiration. Journal of Neuroscience. 2018 May 30;38(22):5122-5139. https://doi.org/10.1523/JNEUROSCI.3652-17.2018