Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F25%3A00638983" target="_blank" >RIV/86652036:_____/25:00638983 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.nature.com/articles/s41467-025-57135-8" target="_blank" >https://www.nature.com/articles/s41467-025-57135-8</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41467-025-57135-8" target="_blank" >10.1038/s41467-025-57135-8</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration

Popis výsledku v původním jazyce

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 (OPTNC) 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.

Název v anglickém jazyce

Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration

Popis výsledku anglicky

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 (OPTNC) 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10601 - Cell biology

Projekt

<a href="/cs/project/EF18_046%2F0015974" target="_blank" >EF18_046/0015974: Modernizace České infrastruktury pro integrativní strukturní biologii</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Nature Communications

ISSN

2041-1723

e-ISSN

2041-1723

Svazek periodika

16

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

23

Strana od-do

1789

Kód UT WoS článku

001509296900026

EID výsledku v databázi Scopus

2-s2.0-85218501739