TY - JOUR
T1 - Structural and functional rescue of chronic metabolically stressed optic nerves through respiration
AU - Harun-Or-Rashid, Mohammad
AU - Pappenhagen, Nate
AU - Palmer, Peter G.
AU - Smith, Matthew A.
AU - Gevorgyan, Victoria
AU - Wilson, Gina N.
AU - Crish, Samuel D.
AU - Inman, Denise M.
N1 - Publisher Copyright:
© 2018 the authors.
PY - 2018/5/30
Y1 - 2018/5/30
N2 - 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.
AB - 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.
KW - B-hydroxybutyrate
KW - Ketogenic diet
KW - Neural-glial interaction
KW - Optic nerve
UR - http://www.scopus.com/inward/record.url?scp=85050811316&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.3652-17.2018
DO - 10.1523/JNEUROSCI.3652-17.2018
M3 - Article
C2 - 29760184
AN - SCOPUS:85050811316
SN - 0270-6474
VL - 38
SP - 5122
EP - 5139
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 22
ER -