Glaucoma-associated Optineurin mutations increase transcellular degradation of mitochondria in a vertebrate optic nerve
Year: 2025
Type: article
Abstract: We previously described a process referred to as transmitophagy where 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 few large- effect glaucoma genes and axonal damage occurs at the optic nerve head in glaucoma, here we explored whether OPTN mutations perturb transmitophagy. 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 support the view that in RGC axons under baseline conditions there are low levels of mitophagy, but that glaucoma-associated perturbations in OPTN result in increased axonal mitophagy involving the shedding and astrocytic degradation of the mitochondria. Graphical Abstract
Source: eLife
DOI: 10.7554/elife.103844
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: NeuroNex: Enabling Identification and Impact of Synaptic Weight in Functional Networks, G1315484480, G140848689, G1795544006, G2495232337, G2853257460, G3301016094, G3308216879, G3748818132, FEI TITAN HALO 300kV INTERMEDIATE VOLTAGE ELECTRON MICROSCOPE, G6273811891, G750410379, G9000083407, G9000132587, G9000324483, VISION RESEARCH CORE GRANT, National Center for Microscopy and Imaging Research: A BRAIN Technology Integration and Dissemination Resource, Initiative for Maximizing Student Development at the University of California, Davis., The UC Davis enhanced Molecular, Cellular, and Developmental Biology Training Program
OpenAlex ID: W4413105142