Inhibition of cAMPPKA Pathway Protects Optic Nerve Head Astrocytes against Oxidative Stress by AktBax Phosphorylation-Mediated Mfn12 Oligomerization
Joint Authors
Ju, Won-Kyu
Shim, Myoung Sup
Kim, Keun-Young
Park, Tae Lim
Ahn, Sangphil
Edwards, Genea
Weinreb, Robert Neal
Source
Oxidative Medicine and Cellular Longevity
Issue
Vol. 2019, Issue 2019 (31 Dec. 2019), pp.1-16, 16 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2019-11-06
Country of Publication
Egypt
No. of Pages
16
Main Subjects
Abstract EN
Glaucoma is characterized by a progressive optic nerve degeneration and retinal ganglion cell loss, but the underlying biological basis for the accompanying neurodegeneration is not known.
Accumulating evidence indicates that structural and functional abnormalities of astrocytes within the optic nerve head (ONH) have a role in glaucomatous neurodegeneration.
Here, we investigate the impact of activation of cyclic adenosine 3′,5′-monophosphate (cAMP)/protein kinase A (PKA) pathway on mitochondrial dynamics of ONH astrocytes exposed to oxidative stress.
ONH astrocytes showed a significant loss of astrocytic processes in the glial lamina of glaucomatous DBA/2J mice, accompanied by basement membrane thickening and collagen deposition in blood vessels and axonal degeneration.
Serial block-face scanning electron microscopy data analysis demonstrated that numbers of total and branched mitochondria were significantly increased in ONH astrocytes, while mitochondrial length and volume density were significantly decreased.
We found that hydrogen peroxide- (H2O2-) induced oxidative stress compromised not only mitochondrial bioenergetics by reducing the basal and maximal respiration but also balance of mitochondrial dynamics by decreasing dynamin-related protein 1 (Drp1) protein expression in rat ONH astrocytes.
In contrast, elevated cAMP by dibutyryl-cAMP (dbcAMP) or isobutylmethylxanthine treatment significantly increased Drp1 protein expression in ONH astrocytes.
Elevated cAMP exacerbated the impairment of mitochondrial dynamics and reduction of cell viability to oxidative stress in ONH astrocytes by decreasing optic atrophy type 1 (OPA1), and mitofusin (Mfn)1/2 protein expression.
Following combined treatment with H2O2 and dbcAMP, PKA inhibition restored mitochondrial dynamics by increasing mitochondrial length and decreasing mitochondrial number, and this promoted cell viability in ONH astrocytes.
Also, PKA inhibition significantly promoted Akt/Bax phosphorylation and Mfn1/2 oligomerization in ONH astrocytes.
These results suggest that modulation of the cAMP/PKA signaling pathway may have therapeutic potential by activating Akt/Bax phosphorylation and promoting Mfn1/2 oligomerization in glaucomatous ONH astrocytes.
American Psychological Association (APA)
Ju, Won-Kyu& Shim, Myoung Sup& Kim, Keun-Young& Park, Tae Lim& Ahn, Sangphil& Edwards, Genea…[et al.]. 2019. Inhibition of cAMPPKA Pathway Protects Optic Nerve Head Astrocytes against Oxidative Stress by AktBax Phosphorylation-Mediated Mfn12 Oligomerization. Oxidative Medicine and Cellular Longevity،Vol. 2019, no. 2019, pp.1-16.
https://search.emarefa.net/detail/BIM-1205429
Modern Language Association (MLA)
Ju, Won-Kyu…[et al.]. Inhibition of cAMPPKA Pathway Protects Optic Nerve Head Astrocytes against Oxidative Stress by AktBax Phosphorylation-Mediated Mfn12 Oligomerization. Oxidative Medicine and Cellular Longevity No. 2019 (2019), pp.1-16.
https://search.emarefa.net/detail/BIM-1205429
American Medical Association (AMA)
Ju, Won-Kyu& Shim, Myoung Sup& Kim, Keun-Young& Park, Tae Lim& Ahn, Sangphil& Edwards, Genea…[et al.]. Inhibition of cAMPPKA Pathway Protects Optic Nerve Head Astrocytes against Oxidative Stress by AktBax Phosphorylation-Mediated Mfn12 Oligomerization. Oxidative Medicine and Cellular Longevity. 2019. Vol. 2019, no. 2019, pp.1-16.
https://search.emarefa.net/detail/BIM-1205429
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1205429