advertisement
Abstract #80532 Published in IGR 20-3
Mitochondrial Uncoupling Protein 2 Knock-out Promotes Mitophagy to Decrease Retinal Ganglion Cell Death in a Mouse Model of Glaucoma
Hass DT; Hass DT; Barnstable CJJournal of Neuroscience 2019; 39: 3582-3596
Glaucoma is a neurodegenerative disorder characterized by mitochondrial dysfunction and an increase in oxidative damage, leading to retinal ganglion cell (RGC) death. The oxidative status of RGCs is regulated intrinsically and also extrinsically by retinal glia. The mitochondrial uncoupling protein 2 (UCP2) relieves oxidative and neuronal damage in a variety of neurodegenerative disease models. We hypothesized that deletion of in either RGCs or retinal glia would increase retinal damage and RGC death in a mouse model of glaucoma. Paradoxically, we found the reverse, and deletion of mitochondrial decreased oxidative protein modification and reduced RGC death in male and female mice. This paradox was resolved after finding that deletion also increased levels of mitophagy in cell culture and retinal tissue. Our data suggest that deletion facilitates increased mitochondrial function by improving quality control. An increase in mitochondrial function explains the resistance of -deleted retinas to glaucoma and may provide a therapeutic avenue for other chronic neurodegenerative conditions. Many unsolved neurodegenerative conditions result from defects in mitochondrial function. Molecular tools that can manipulate mitochondria will therefore be central to developing neuroprotective therapies. Among the most potent regulators of mitochondrial function are the uncoupling proteins, particularly UCP2. In this manuscript, we show that, while loss of does increase mitochondrial membrane potential and the production of reactive oxygen species, it also initiates an increase in mitophagy that is ultimately neuroprotective. This novel protective consequence of uncoupling protein inhibition may lead to new therapeutic approaches to combat neurodegenerative disease, particularly because pharmacological compounds do exist that can selectively inhibit UCP2.
Department of Neural and Behavioral Sciences, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033.
Full articleClassification:
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)
11.8 Neuroprotection (Part of: 11 Medical treatment)
3.8 Pharmacology (Part of: 3 Laboratory methods)
