Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration

Dong Liu, Hannah C. Webber, Fuyun Bian, Yangfan Xu, Manjari Prakash, Xue Feng, Ming Yang, Hang Yang, In-Jee You, Liang Li, Liping Liu, Pingting Liu, Haoliang Huang, Chien-Yi Chang, Liang Liu, Sahil H. Shah, Anna Torre, Derek S. Welsbie, Yang Sun, Xin Duan, Jeffrey Louis Goldberg, Marcus Braun, Zdenek Lansky (zdenek.lansky@ibt.cas.cz) and Yang Hu (huyang@stanford.edu)
Additional contact information
Dong Liu: Byers Eye Institute at Stanford University School of Medicine
Hannah C. Webber: Byers Eye Institute at Stanford University School of Medicine
Fuyun Bian: Byers Eye Institute at Stanford University School of Medicine
Yangfan Xu: Byers Eye Institute at Stanford University School of Medicine
Manjari Prakash: Vestec
Xue Feng: Byers Eye Institute at Stanford University School of Medicine
Ming Yang: Byers Eye Institute at Stanford University School of Medicine
Hang Yang: Byers Eye Institute at Stanford University School of Medicine
In-Jee You: Byers Eye Institute at Stanford University School of Medicine
Liang Li: Byers Eye Institute at Stanford University School of Medicine
Liping Liu: Byers Eye Institute at Stanford University School of Medicine
Pingting Liu: Byers Eye Institute at Stanford University School of Medicine
Haoliang Huang: Byers Eye Institute at Stanford University School of Medicine
Chien-Yi Chang: Stanford University
Liang Liu: Byers Eye Institute at Stanford University School of Medicine
Sahil H. Shah: Byers Eye Institute at Stanford University School of Medicine
Anna Torre: University of California
Derek S. Welsbie: University of California San Diego
Yang Sun: Byers Eye Institute at Stanford University School of Medicine
Xin Duan: University of California San Francisco
Jeffrey Louis Goldberg: Byers Eye Institute at Stanford University School of Medicine
Marcus Braun: Vestec
Zdenek Lansky: Vestec
Yang Hu: Byers Eye Institute at Stanford University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We find that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a decrease of axonal mitochondria in mice. We discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Furthermore, overexpressing OPTN/TRAK1/KIF5B prevents not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes robust ON regeneration. Therefore, in addition to generating animal models for NTG and ALS, our results establish OPTN as a facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.

Date: 2025
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DOI: 10.1038/s41467-025-57135-8

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