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Reduced Zn2+ promotes retinal ganglion cells survival and optic nerve regeneration after injury through inhibiting autophagy mediated by ROS/Nrf2

The molecular mechanism of how reduced mobile zinc (Zn2+) affected retinal ganglion cell (RGC) survival and optic nerve regeneration after optic nerve crush (ONC) injury remains unclear. Here, we used conditionally knocked out ZnT-3 in the amacrine cells (ACs) of mice (CKO) in order to explore the role of reactive oxygen species (ROS), nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2) and autophagy in the protection of RGCs and axon regeneration after ONC injury. We found that reduced Zn2+ can promote RGC survival and axonal regeneration by decreasing ROS, activating Nrf2, and inhibiting autophagy. Additionally, autophagy after ONC is regulated by ROS and Nrf2. Visual function in mice after ONC injury was partially recovered through the reduction of Zn2+, achieved by using a Zn2+ specific chelator N,N,N',N'-tetrakis-(2-Pyridylmethyl) ethylenediamine (TPEN) or through CKO mice. Overall, our data reveal the crosstalk between Zn2+, ROS, Nrf2, and autophagy following ONC injury. This study verified that TPEN or knocking out ZnT-3 in ACs is a promising therapeutic option for the treatment of optic nerve damage and elucidated the postsynaptic molecular mechanism of Zn2+-triggered damage to RGCs after ONC injury.

 

Comments:

It sounds like you're summarizing a study that investigates the impact of reduced mobile zinc (Zn2+) on retinal ganglion cell (RGC) survival and optic nerve regeneration post-optic nerve crush (ONC) injury in mice. The study focuses on the role of ZnT-3, a zinc transporter protein, specifically knocked out in amacrine cells (ACs), aiming to understand the involvement of reactive oxygen species (ROS), nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2), and autophagy in protecting RGCs and promoting axon regeneration after ONC injury.

The findings indicate that decreased Zn2+ levels contribute to enhanced RGC survival and axonal regeneration by reducing ROS levels, activating Nrf2, and inhibiting autophagy. Moreover, the study suggests that ROS and Nrf2 play significant roles in regulating autophagy following ONC. The use of a Zn2+ specific chelator, N,N,N',N'-tetrakis-(2-Pyridylmethyl) ethylenediamine (TPEN), or the conditional knockout of ZnT-3 in ACs in mice resulted in partial recovery of visual function post-ONC injury.

This research sheds light on the interplay between Zn2+, ROS, Nrf2, and autophagy following ONC injury and proposes that TPEN administration or ZnT-3 knockout in ACs could be a promising therapeutic approach for treating optic nerve damage. Additionally, it contributes to understanding the molecular mechanism underlying Zn2+-related damage to RGCs after ONC injury.

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TPEN (TPEDA) is a specific cell-permeable heavy metal chelator that induces apoptosis in NB4 cells via negatively regulating intracellular NO and Zn2+ signaling. TPEN (TPEDA) may be a potential therapeutic strategy for APL (acute promyelocytic leukemia).TPEN induces DNA damage and increases intracellular ROS production and also inhibits cell proliferation.

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