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.