Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration
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.
Authors
- Liang Liu (ORCID: https://orcid.org/0000-0002-5379-0638)
- Marcus Braun (ORCID: https://orcid.org/0000-0003-2026-2238)
- Zdeněk Lánský (ORCID: https://orcid.org/0000-0001-8474-053X)
- Xin Duan (ORCID: https://orcid.org/0000-0001-5260-8972)
- Manjari Prakash
- Sahil Shah (ORCID: https://orcid.org/0000-0002-6601-219X)
- In‐Jee You (ORCID: https://orcid.org/0000-0002-6557-5337)
- Yang Sun (ORCID: https://orcid.org/0000-0001-8735-4765)
- Liang Li
- Anna La Torre (ORCID: https://orcid.org/0000-0003-2103-4376)
- Yang Hu (ORCID: https://orcid.org/0000-0002-7980-1649)
- Chien-Yi Chang (ORCID: https://orcid.org/0000-0001-6508-1161)
- Hannah C. Webber (ORCID: https://orcid.org/0000-0002-5700-4569)
- Fuyun Bian
- Jeffrey L. Goldberg (ORCID: https://orcid.org/0000-0002-1390-7360)
- Derek S. Welsbie (ORCID: https://orcid.org/0000-0002-3772-9335)
- Pingting Liu (ORCID: https://orcid.org/0000-0003-1601-2818)
- Liping Liu (ORCID: https://orcid.org/0000-0001-6356-0978)
- Dong Liu
- Hang Yang (ORCID: https://orcid.org/0000-0001-8316-6572)
- Ming Wen Ou Yang (ORCID: https://orcid.org/0000-0002-0417-8258)
- Yangfan Xu (ORCID: https://orcid.org/0000-0003-1531-5737)
- Xue Feng (ORCID: https://orcid.org/0000-0002-9624-9665)
- Haoliang Huang (ORCID: https://orcid.org/0000-0002-6856-3956)
Institutions
- University of California, San Francisco (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- University of California San Diego (US)
- Czech Academy of Sciences, Institute of Biotechnology (CZ)
- Eye & ENT Hospital of Fudan University (CN)
- University of California, Davis (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-20
- DOI
- https://doi.org/10.1038/s41467-025-57135-8
- Citations
- 17
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 13.70
Funders
- Glaucoma Research Foundation
- Research to Prevent Blindness
- National Natural Science Foundation of China
- Ministerstvo Školství, Mládeže a Tělovýchovy
- Grantová Agentura České Republiky
- National Institutes of Health
- National Eye Institute
- National Center for Research Resources