Increased Mobile Zinc Regulates Retinal Ganglion Cell Survival via Activating Mitochondrial OMA1 and Integrated Stress Response

Retinal ganglion cells (RGCs), the projection neurons of the eye, are irreversibly lost once the optic nerve is injured, which is a critical mechanism of glaucoma. Mobile zinc (Zn(2+)) levels rapidly increase in retinal interneuron amacrine cells and Zn(2+) is then transferred to RGCs via the Zn(2+) transporter protein ZnT-3, triggering RGC loss in optic nerve injury. Zn(2+) chelation and ZnT-3 deletion promote long-term RGC survival. However, the downstream signaling pathways of Zn(2+) in RGCs remains unknown. Here, we show that increased levels of Zn(2+) upregulate the expression and activity of mitochondrial zinc metallopeptidase OMA1 in the retina, leading to the cleavage of DELE1 and activation of cytosolic eIF2α kinase PKR, triggering the integrated stress response (ISR) in RGCs. Our study identified OMA1 and ISR as the downstream molecular mechanisms of retinal Zn(2+) and potential targets for preventing the progression of Zn(2+)-associated neuronal damage.