TY - JOUR
T1 - MCT2 overexpression rescues metabolic vulnerability and protects retinal ganglion cells in two models of glaucoma
AU - Harun-Or-Rashid, Mohammad
AU - Pappenhagen, Nathaniel
AU - Zubricky, Ryan
AU - Coughlin, Lucy
AU - Jassim, Assraa Hassan
AU - Inman, Denise M.
N1 - Funding Information:
This work was supported by the National Institutes of Health [ EY-026662 to DMI], United States of America.
Publisher Copyright:
© 2020 The Authors
PY - 2020/7
Y1 - 2020/7
N2 - Improving cellular access to energy substrates is one strategy to overcome observed declines in energy production and utilization in the aged and pathologic central nervous system. Monocarboxylate transporters (MCTs), the movers of lactate, pyruvate, and ketone bodies into or out of a cell, are significantly decreased in the DBA/2 J mouse model of glaucoma. In order to confirm MCT decreases are disease-associated, we decreased MCT2 in the retinas of MCT2fl/+ mice using an injection of AAV2-cre, observing significant decline in ATP production and visual evoked potential. Restoring MCT2 levels in retinal ganglion cells (RGCs) via intraocular injection of AAV2-GFP-MCT2 in two models of glaucoma, the DBA/2 J (D2), and a magnetic bead model of ocular hypertension (OHT), preserved RGCs and their function. Viral-mediated overexpression of MCT2 increased RGC density and axon number, reduced energy imbalance, and increased mitochondrial function as measured by cytochrome c oxidase and succinate dehydrogenase activity in both models of glaucoma. Ocular hypertensive mice injected with AAV2:MCT2 had significantly greater P1 amplitude as measured by pattern electroretinogram than mice with OHT alone. These findings indicate overexpression of MCT2 improves energy homeostasis in the glaucomatous visual system, suggesting that expanding energy input options for cells is a viable option to combat neurodegeneration.
AB - Improving cellular access to energy substrates is one strategy to overcome observed declines in energy production and utilization in the aged and pathologic central nervous system. Monocarboxylate transporters (MCTs), the movers of lactate, pyruvate, and ketone bodies into or out of a cell, are significantly decreased in the DBA/2 J mouse model of glaucoma. In order to confirm MCT decreases are disease-associated, we decreased MCT2 in the retinas of MCT2fl/+ mice using an injection of AAV2-cre, observing significant decline in ATP production and visual evoked potential. Restoring MCT2 levels in retinal ganglion cells (RGCs) via intraocular injection of AAV2-GFP-MCT2 in two models of glaucoma, the DBA/2 J (D2), and a magnetic bead model of ocular hypertension (OHT), preserved RGCs and their function. Viral-mediated overexpression of MCT2 increased RGC density and axon number, reduced energy imbalance, and increased mitochondrial function as measured by cytochrome c oxidase and succinate dehydrogenase activity in both models of glaucoma. Ocular hypertensive mice injected with AAV2:MCT2 had significantly greater P1 amplitude as measured by pattern electroretinogram than mice with OHT alone. These findings indicate overexpression of MCT2 improves energy homeostasis in the glaucomatous visual system, suggesting that expanding energy input options for cells is a viable option to combat neurodegeneration.
KW - Glaucoma
KW - Metabolism
KW - Monocarboxylate transporter
KW - Ocular hypertension
KW - Retinal ganglion cell
UR - http://www.scopus.com/inward/record.url?scp=85084857554&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2020.104944
DO - 10.1016/j.nbd.2020.104944
M3 - Article
C2 - 32422282
AN - SCOPUS:85084857554
SN - 0969-9961
VL - 141
JO - Neurobiology of Disease
JF - Neurobiology of Disease
M1 - 104944
ER -