Mitochondrial Protection in Glaucomatous Optic Neuropathy

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Glaucoma is a leading cause of blindness worldwide in individuals 60 years of age and older. Glaucomatous neurodegeneration is associated with impaired mitochondrial network, oxidative stress and mitochondrial dysfunction. Primary open angle glaucoma, in particular, is linked to polymorphism of mitochondrial cytochrome c oxidase (COX) subunit I of the oxidative phosphorylation (OXPHOS) complex (Cx)-IV and impaired OXPHOS Cx-I-linked respiration activity and adenosine triphosphate (ATP) synthesis. Therefore a role for compromised OXPHOS in pathogenesis of glaucoma is suggested, although the contribution of an impaired mitochondrial network to glaucoma is poorly understood. A-kinase anchoring protein 1 (AKAP1) is an outer mitochondrial membrane-targeted AKAP that regulates mitochondrial dynamics and contributes to mitochondrial network, bioenergetics and calcium homeostasis. Recently, our group has discovered that neuronal AKAP1 has potent neuroprotective properties through inhibition of mitochondrial fission dynamin-related protein 1 (Drp1), which suggests that modulation of AKAP1 could be a therapeutic approach to mitochondrial dysfunction and glaucomatous neurodegeneration. Our preliminary studies showed that 1) elevated intraocular pressure (IOP) induced loss of AKAP1, activation of calcineurin (CaN) and dephosphorylation of Drp1 at Ser637; 2) loss of AKAP1 increased CaN and total Drp1 level, and decreased Drp1 phosphorylation at Ser637 in the retina; 3) loss of AKAP1 further triggered mitochondrial fragmentation and loss, and induced mitophagosome formation in retinal ganglion cells (RGCs); 4) loss of AKAP1 deregulated OXPHOS Cxs by increasing Cx-II and decreasing Cx-III-V in the retina, leading to metabolic and oxidative stress; 5) loss of AKAP1 decreased Akt phosphorylation and activated the Bim/Bax signaling pathway in the retina; and 6) overexpression of AKAP1 led to enhanced mitochondrial activity and blocked apoptosis in RGCs, and promoted RGC survival in the setting of oxidative stress. Altogether, these findings suggest a critical role of AKAP1 in RGC protection and lead us to hypothesize that AKAP1 overexpression protects RGCs from the effects of glaucoma by promoting mitochondrial network, bioenergetics and structural integrity. We will test whether AKAP1 deficiency and its disruption of the signaling nexus impinging on mitochondria contribute to the impairment of mitochondrial bioenergetics and structure in RGCs. We will also test the protective effect of AKAP1 overexpression on mitochondrial bioenergetics and structure in glaucomatous RGCs and the therapeutic potential of AKAP1 overexpression on the central visual pathway and vision. We anticipate that these studies will enhance understanding of how AKAP1 regulates mitochondrial transport, network dynamics and bioenergetics and will support AKAP1 overexpression as a strategy to induce neuroprotection against glaucoma and optic neuropathies by improving central visual pathway functions and vision.