Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fragmentation and loss in retinal ganglion cells

Edwards, G.; Perkins, G. A.; Kim, K.-Y.; Kong, Y.; Lee, Y.; Choi, S.-H.; Skowronska-Krawczyk, D.; Weinreb, R. N.; Zangwill, L.; Strack, S.; Ju, W.-K.

doi:10.1101/790139

bioRxiv · 10.1101/790139

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fragmentation and loss in retinal ganglion cells

Edwards, G.·Perkins, G. A.·Kim, K.-Y.·Kong, Y.·Lee, Y.·Choi, S.-H.·Skowronska-Krawczyk, D.·Weinreb, R. N.·Zangwill, L.·Strack, S.·Ju, W.-K.

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Abstract

Impairment of mitochondrial structure and function is strongly linked to glaucoma pathogenesis. Despite the widely appreciated disease relevance of mitochondrial dysfunction and loss, the molecular mechanisms underlying mitochondrial fragmentation and metabolic stress in glaucoma are poorly understood. We demonstrate here that glaucomatous retinal ganglion cells (RGCs) show loss of A-kinase anchoring protein 1 (AKAP1), activation of calcineurin (CaN) and reduction of dynamin-related protein 1 (Drp1) phosphorylation at serine 637 (Ser637). These findings suggest that AKAP1-mediated phosphorylation of Drp1 at Ser637 has a critical role in RGC survival in glaucomatous neurodegeneration. Male mice lacking AKAP1 show increases of CaN and total Drp1 level, as well as a decrease of Drp1 phosphorylation at Ser637 in the retina. Ultrastructural analysis of mitochondria shows that loss of AKAP1 triggers mitochondrial fragmentation and loss, as well as mitophagosome formation in RGCs. Loss of AKAP1 deregulates oxidative phosphorylation (OXPHOS) complexes (Cxs) by increasing CxII and decreasing CxIII-V, leading to metabolic and oxidative stress. Also, loss of AKAP1 decreases Akt phosphorylation at Serine 473 (Ser473) and threonine 308 (Thr308) and activates the Bim/Bax signaling pathway in the retina. These results suggest that loss of AKAP1 has a critical role in RGC dysfunction by decreasing Drp1 phosphorylation at Ser637, deregulating OXPHOS, decreasing Akt phosphorylation at Ser473 and Thr308, and activating the Bim/Bax pathway in glaucomatous neurodegeneration. Thus, we propose that overexpression of AKAP1 or modulation of Drp1 phosphorylation at Ser637 are potential therapeutic strategies for neuroprotective intervention in glaucoma and other mitochondria-related optic neuropathies.

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Edwards, G., Perkins, G. A., Kim, K.-Y., Kong, Y., Lee, Y., Choi, S.-H., Skowronska-Krawczyk, D., Weinreb, R. N., Zangwill, L., Strack, S., Ju, W.-K.. 2019-10-02. Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fragmentation and loss in retinal ganglion cells. https://doi.org/10.1101/790139

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