Mitochondrial Uncoupling Protein 2 (UCP2) Regulates Retinal Ganglion Cell Number and Survival

Abstract

In the brain, mitochondrial uncoupling protein 2 (UCP2) has emerged as a stress signal associated with neuronal survival. In the retina UCP2 is expressed primarily by retinal ganglion cells. Here we investigated the functional relevance of UCP2 in the mouse retina. Increased expression of UCP2 significantly reduced apoptosis during the critical developmental period resulting in elevated numbers of retinal ganglion cells in the adult. Elevated UCP2 levels also protected against excitotoxic cell death induced by intraocular injection of either NMDA or Kainic Acid. In monolayer cultures of retinal cells, elevated UCP2 levels increased cell survival and rendered the cells independent of the survival promoting effects of the neurotrophic factors BDNF and CNTF. Taken together these data implicate UCP2 as an important regulator of retinal neuron survival both during development and in adult animals.

Mitochondrial Uncoupling Protein 2 Knockout Promotes Mitophagy to Decrease Retinal Ganglion Cell Death in a Mouse Model of Glaucoma

“…Previous studies have shown that greater levels of Ucp2 expression are protective against various conditions that increase oxidative stress, including excitotoxicity and MPTP-induced parkinsonism (Diano et al, 2003;Andrews et al, 2005;Barnstable et al, 2016). We have found that UCP2 is highly expressed in the inner retina (Fig.…”

“…4-5). This finding, while not unprecedented (de Bilbao et al, 2004), was surprising, as Ucp2 overexpression is neuroprotective in retinas exposed to excitotoxic factors (Barnstable et al, 2016) and the reverse genetic manipulation was expected to have the opposite effect. To determine the source of the observed neuroprotective phenotype, we monitored the mitochondrial morphology of Ucp2-deficient cells.…”

“…UCP2 activity decreases electron transport chain efficiency, increasing energy expenditure (Zhang et al, 2001) and decreasing ROS generation (Nègre-Salvayre et al, 1997;Arsenijevic et al, 2000). UCP2-mediated uncoupling of mitochondria is cytoprotective under a variety of stressful conditions (Mattiasson et al, 2003;Andrews et al, 2005;Barnstable et al, 2016). As a consequence of Ucp2 deletion, mice generate more ROS and are increasingly susceptible to cell death following acute exposure to stressors such as the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Andrews et al, 2005) or focal ischemia (Haines et al, 2010).…”

“…As a consequence of Ucp2 deletion, mice generate more ROS and are increasingly susceptible to cell death following acute exposure to stressors such as the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Andrews et al, 2005) or focal ischemia (Haines et al, 2010). Notably, Ucp2 deletion can be protective (de Bilbao et al, 2004), deleterious (Andrews et al, 2005;Haines et al, 2010), or have no clear effect on cell survival (Barnstable et al, 2016) in different models of neurodegeneration.…”

Mitochondrial Uncoupler Prodrug of 2,4‐Dinitrophenol, MP201, Prevents Neuronal Damage and Preserves Vision in Experimental Optic Neuritis

“…A recent study showed that mitochondrial uncoupling achieved by overexpression of UCP2 protected RGCs from glutamate excitotoxicity [29]. Thus, we hypothesized that MP201 may have similar neuroprotective properties that suppress RGC loss in optic neuritis and improve visual outcomes.…”