Role of A-Kinase Anchoring Protein 1 in Retinal Ganglion Cells: Neurodegeneration and Neuroprotection

Abstract

A-Kinase anchoring protein 1 (AKAP1) is a multifunctional mitochondrial scaffold protein that regulates mitochondrial dynamics, bioenergetics, and calcium homeostasis by anchoring several proteins, including protein kinase A, to the outer mitochondrial membrane. Glaucoma is a complex, multifactorial disease characterized by a slow and progressive degeneration of the optic nerve and retinal ganglion cells (RGCs), ultimately resulting in vision loss. Impairment of the mitochondrial network and function is linked to glaucomatous neurodegeneration. Loss of AKAP1 induces dynamin-related protein 1 dephosphorylation-mediated mitochondrial fragmentation and loss of RGCs. Elevated intraocular pressure triggers a significant reduction in AKAP1 protein expression in the glaucomatous retina. Amplification of AKAP1 expression protects RGCs from oxidative stress. Hence, modulation of AKAP1 could be considered a potential therapeutic target for neuroprotective intervention in glaucoma and other mitochondria-associated optic neuropathies. This review covers the current research on the role of AKAP1 in the maintenance of mitochondrial dynamics, bioenergetics, and mitophagy in RGCs and provides a scientific basis to identify and develop new therapeutic strategies that could protect RGCs and their axons in glaucoma.

Keywords: AKAP1; DRP1; glaucoma; mitochondrial dynamics; mitochondrial fission; neurodegeneration; neuroprotection; retinal ganglion cell.

Figure 1

Schematic diagram of full-length AKAP1 protein in humans and mice. The different color boxes represent the different protein domains of full-length AKAP1 (Blue), indicated as N-terminal MT domain (Red), PP1 binding domain (Orange), PKA binding domain (Green), C-terminal mRNA binding KH domain (Purple) and Tudor domain (Yellow). Its domain structure sheds light on the molecular mechanisms by which AKAP1 modulates many cellular signaling pathways.

Figure 2

Role of AKAP1 in regulation of mitochondrial biogenesis, dynamics, bioenergetics, and mitophagy. (A) AKAP1 influences mitochondrial biogenesis through the activation of PGC-1α, leading to increased production of mitochondrial proteins such as TFAM to promote mitochondrial biogenesis. Along with AKAP1, Ca²⁺ and AMP/ATP activity also promote mitochondrial biogenesis. (B,C) AKAP1 contributes to mitochondrial dynamics and bioenergetics. Specifically, it inhibits mitochondrial fission activity by preventing the activation of DRP1 through phosphorylation of the DRP1 S637 site. On the other hand, AKAP1 promotes mitochondrial fusion activity, which is mediated by OPA1 and MFN1/2. AKAP1 also promotes ATP synthesis by regulating OXPHOS complexes, resulting in balanced mitochondrial bioenergetics. (D) AKAP1 influences mitophagy mediated by the PINK1/Parkin pathway, where PINK1 accumulates in damaged mitochondria and recruits Parkin to degrade mitochondria through ubiquitination, which then promotes the formation of autophagosomes and eliminates the damaged mitochondria.

Figure 3

Neuroprotective effect of AKAP1 in glaucomatous RGCs. The upper panel diagrams the effect of glaucomatous insults such as elevated IOP in RGCs. Glaucomatous insults cause mitochondrial stress in RGCs, resulting in the loss of AKAP1, which triggers excessive mitochondrial fission through activation of DRP1 and the subsequent proapoptotic pathway BIM/BAX. This exacerbates mitochondrial dysfunction, ultimately leading to RGC death and a vision defect. The lower panel diagrams how restoring sustained AKAP1 expression in RGCs by intravitreal delivery of AAV2-AKAP1 protects RGCs by increasing phosphorylation of DRP1 S637, which promotes visual function in glaucomatous neurodegeneration.