PT - JOURNAL ARTICLE AU - Daniel T Hass AU - Colin J Barnstable TI - Mitochondrial Uncoupling Protein 2 Knockout Promotes Mitophagy to Decrease Retinal Ganglion Cell Death in a Mouse Model of Glaucoma AID - 10.1101/465153 DP - 2019 Jan 01 TA - bioRxiv PG - 465153 4099 - http://biorxiv.org/content/early/2019/01/16/465153.short 4100 - http://biorxiv.org/content/early/2019/01/16/465153.full AB - 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 Ucp2 in either RGCs or retinal glia would increase retinal damage and retinal ganglion cell death in a mouse model of glaucoma. Paradoxically, we found the reverse, and deletion of mitochondrial UCP2 decreased oxidative protein modification and reduced retinal ganglion cell death in male and female mice. This paradox was resolved after finding that Ucp2 deletion also increased levels of mitophagy in cell culture and retinal tissue. Our data suggest that Ucp2 deletion facilitates increased mitochondrial function by improving quality control. An increase in mitochondrial function explains the resistance of Ucp2-deleted retinas to glaucoma and may provide a therapeutic avenue for other chronic neurodegenerative conditions.Significance Statement 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 UCP2 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.This work was supported by grants from the National Institutes of Health and the Macula Vision Research Foundation. The authors thank Angela Snyder for providing the mouse cartoon used in figures 1 and 3, as well as Drs Evgenya Popova, Gregory Yochum, and Ian Simpson for their critical review of and intellectual contributions to this manuscript.