Mitochondrial Protection by Exogenous Otx2 in Mouse Retinal Neurons

• Otx2 haplodeficiency results in retinal dystrophy in mice
• Otx2 proteins from photoreceptors are protective of retinal bipolar cells
• Exogenous Otx2 in bipolar cells is found into mitochondria and affects ATP synthesis
• Intraocular Otx2 injection restores retinal activity in Otx2−/+ mice

SummaryOTX2 (orthodenticle homeobox 2) haplodeficiency causes diverse defects in mammalian visual systems ranging from retinal dysfunction to anophthalmia. We find that the retinal dystrophy of Otx2+/GFP heterozygous knockin mice is mainly due to the loss of bipolar cells and consequent deficits in retinal activity. Among bipolar cell types, OFF-cone bipolar subsets, which lack autonomous Otx2 gene expression but receive Otx2 proteins from photoreceptors, degenerate most rapidly in Otx2+/GFP mouse retinas, suggesting a neuroprotective effect of the imported Otx2 protein. In support of this hypothesis, retinal dystrophy in Otx2+/GFP mice is prevented by intraocular injection of Otx2 protein, which localizes to the mitochondria of bipolar cells and facilitates ATP synthesis as a part of mitochondrial ATP synthase complex. Taken together, our findings demonstrate a mitochondrial function for Otx2 and suggest a potential therapeutic application of OTX2 protein delivery in human retinal dystrophy.

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