Cumulative mtDNA damage and mutations contribute to the progressive loss of RGCs in a rat model of glaucoma
| Autor: | Ji-hong Wu, Sheng-hai Zhang, John M. Nickerson, Feng-juan Gao, Zhongmou Sun, Xin-ya Chen, Shu-jie Zhang, Rong Zhang, Feng Gao, Jun-yi Chen, Yi Luo, Yan Wang, Xing-huai Sun |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Retinal Ganglion Cells Mitochondrial DNA Time Factors genetic structures DNA Repair DNA damage DNA repair Cell Survival Glaucoma Glutamic Acid Apoptosis Mitochondrion Biology medicine.disease_cause Retinal ganglion DNA Mitochondrial Article lcsh:RC321-571 medicine Animals Retinal ganglion cell Rats Wistar lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Intraocular Pressure Genetics Mutation Optic Nerve medicine.disease eye diseases Axons Mitochondria Disease Models Animal medicine.anatomical_structure Neurology Cancer research Disease Progression sense organs DNA Damage |
| Zdroj: | Neurobiology of Disease, Vol 74, Iss, Pp 167-179 (2015) |
| ISSN: | 1095-953X |
| Popis: | Glaucoma is a chronic neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Mitochondrial DNA (mtDNA) alterations have been documented as a key component of many neurodegenerative disorders. However, whether mtDNA alterations contribute to the progressive loss of RGCs and the mechanism whereby this phenomenon could occur are poorly understood. We investigated mtDNA alterations in RGCs using a rat model of chronic intraocular hypertension and explored the mechanisms underlying progressive RGC loss. We demonstrate that the mtDNA damage and mutations triggered by intraocular pressure (IOP) elevation are initiating, crucial events in a cascade leading to progressive RGC loss. Damage to and mutation of mtDNA, mitochondrial dysfunction, reduced levels of mtDNA repair/replication enzymes, and elevated reactive oxygen species form a positive feedback loop that produces irreversible mtDNA damage and mutation and contributes to progressive RGC loss, which occurs even after a return to normal IOP. Furthermore, we demonstrate that mtDNA damage and mutations increase the vulnerability of RGCs to elevated IOP and glutamate levels, which are among the most common glaucoma insults. This study suggests that therapeutic approaches that target mtDNA maintenance and repair and that promote energy production may prevent the progressive death of RGCs. |
| Databáze: | OpenAIRE |
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