Research Project
10246780
Project summary Degeneration of retinal ganglion cells (RGCs) is the major cause for blindness in optic neuropathies and glaucoma. The degenerated RGCs cannot be repaired, and currently, there are no treatments that regenerate RGCs. Stem cell-derived RGC replacement is likely the only treatment option; however, functional restoration of retina remains challenging and difficult. Neuroprotection is a more practical approach that prevents RGC degeneration and prolongs RGC survival, which can delay vision loss. Retina and optic nerve represent highly energy-demanding systems, requiring proper mitochondrial function. One of the mechanisms of RGC death is excitotoxicity that induces mitochondrial permeability transition (MPT), leading to mitochondrial dysfunction and RGC degeneration. The protein optic atrophy 1 (OPA1) plays a critical role in maintaining mitochondrial function, as mutations in OPA1 gene causes hereditary autosomal dominant optic atrophy. OPA1 is known to have a dual function, mediating fusion of mitochondrial inner membrane (IM) and maintaining cristae structure. In mitochondria, OPA1 exists as IM-anchored long L-OPA1 and short soluble S-OPA1 that is generated by a cleavage of L-OPA1. Although S-OPA1 had been considered a functionally insignificant cleavage product, our recent study demonstrated that S-OPA1 is competent for maintaining mitochondrial function. Importantly, our ongoing studies obtained new evidence that S-OPA1 renders improved cell survival under stress conditions by decreasing MPT. Therefore, in this proposal, we will define the new OPA1 mechanism for regulating MPT and explore its potential application for RGC neuroprotective therapy. Our central hypothesis is that S-OPA1 supports RGC survival under excitotoxic stress by decreasing MPT. We propose two specific aims to test our hypothesis. In Aim 1, we will determine the molecular mechanisms by which L- and S-OPA1 regulate MPT sensitivity. Using L- and S-OPA1-specific cells, we will alter OPA1 cleavage and oligomerization, and evaluate how they change MPT sensitivity and cell death. In aim 2, we will determine whether increasing the S-OPA1 level improves RGC survival under stress. Using virus-mediated gene transfer, we will test the effects of changing the levels of L- and S-OPA1 on RGC survival under excitotoxic stress in vitro and in vivo. This proposal is designed to define a new, third role of OPA1, as an MPT regulator, and to test its therapeutic potential for neuroprotective therapy. New information from the proposed studies will add a novel paradigm to the current understanding of OPA1 function and MPT regulation, and help developing a new strategy for ameliorating RGC degeneration.
