PGC-1α signaling coordinates susceptibility to metabolic and oxidative injury in the inner retina
Open accessAbstract
Retinal ganglion cells (RGCs), used as a common model of central nervous system injury, are particularly vulnerable to metabolic and oxidative damage. However, molecular mechanisms underlying this sensitivity have not been determined in vivo. PGC-1α (encoded by PPARGC1A) regulates adaptive metabolism and oxidative stress responses in a tissue- and cell-specific manner. Aberrant PGC-1α signaling is implicated in neurodegeneration, but the mechanism underlying its role in central nervous system injury remains unclear. We provide evidence from a mouse model that PGC-1α expression and activity are induced in adult retina in response to metabolic and oxidative challenge. Deletion of Ppargc1a dramatically increased RGC loss, in association with dysregulated expression of PGC-1α target metabolic and oxidative stress response genes, including Hmox1 (encoding HO-1), Tfam, and Vegfa. Vehicle-treated and naive Ppargc1a(-/-) mice also showed mild RGC loss, and surprisingly prominent and consistent retinal astrocyte reactivity. These cells critically regulate metabolic homeostasis in the inner retina. We show that PGC-1α signaling (not previously studied in glia) regulates detoxifying astrocyte responses to hypoxic and oxidative stresses. Finally, PGC-1α expression was modulated in the inner retina with age and in a model of chronic optic neuropathy. These data implicate PGC-1α signaling as an important regulator of astrocyte reactivity and RGC homeostasis to coordinate pathogenic susceptibility to metabolic and oxidative injury in the inner retina.
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- Authors
- Guo, X., Dason, E. S., Zanon-Moreno, V., Jiang, Q., Nahirnyj, A., Chan, D., Flanagan, J. G., & Sivak, J. M.
- Affiliations
- University Health Network (CA)
- Corresponding author
- Sivak, Jeremy M.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 184
- Issue
- 4
- Pages
- 1017-1029
- ISSN
- 0002-9440 (ISSN-L)
- OpenAlex
- W2025199189
- Cited by
- 47
- References
- 62
- Citations by year
- 2025: 2 · 2024: 4 · 2023: 3 · 2022: 1 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 8 · 2017: 4 · 2016: 5 · 2015: 6
- FWCI
- 4.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Glaucoma Research Foundation
- Glaucoma Research Society of Canada
- CNIB
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- PGC-1α, retinal ganglion cells, inner retina, astrocyte activation, oxidative stress, metabolic stress, hypoxia, heme oxygenase-1, TFAM, VEGF-A, neurodegeneration, age-related retinal degeneration
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Astrocytes, Humans, Immunohistochemistry, Retinal Ganglion Cells, Transcription Factors, Signal Transduction, In Situ Hybridization, Mice, Knockout, Oxidative Stress, Reverse Transcriptase Polymerase Chain Reaction, In Situ Nick-End Labeling, Mice
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