Glaucoma-associated optineurin mutations increase transcellular degradation of mitochondria in a vertebrate optic nerve

We previously described a process whereby mitochondria shed by retinal ganglion cell (RGC) axons are transferred to and degraded by surrounding astrocytes in the optic nerve head of mice. Since the mitophagy receptor Optineurin (OPTN) is one of the few large-effect glaucoma genes and axonal damage occurs at the optic nerve head in glaucoma, here we explored whether OPTN mutations perturb the transcellular degradation of mitochondria. Live-imaging of Xenopus laevis optic nerves revealed that diverse human mutant but not wildtype OPTN increase stationary mitochondria and mitophagy machinery and their colocalization within, and in the case of the glaucoma-associated OPTN mutations, also outside of, RGC axons. These extra-axonal mitochondria are degraded by astrocytes. Our studies demonstrate that expression of OPTN carrying a glaucoma-associated mutation results in increased transcellular degradation of axonal mitochondria.