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

Genea Edwards; Guy A Perkins; Keun-Young Kim; YeEun Kong; Yonghoon Lee; Soo-Ho Choi; Yujia Liu; Dorota Skowronska-Krawczyk; Robert N Weinreb; Linda Zangwill; Stefan Strack; Won-Kyu Ju

doi:10.1038/s41419-020-2456-6

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

Journal article

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

Genea Edwards, Guy A Perkins, Keun-Young Kim, YeEun Kong, Yonghoon Lee, Soo-Ho Choi, Yujia Liu, Dorota Skowronska-Krawczyk, Robert N Weinreb, Linda Zangwill, …

Cell death & disease, Vol.11(4), pp.254-254

04/20/2020

DOI: 10.1038/s41419-020-2456-6

PMCID: PMC7170863

PMID: 32312949

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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 in CaN and total Drp1 levels, as well as a decrease in 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.

Dynamins - metabolism

Animals

Oxidative Stress - physiology

Mice, Transgenic

Signal Transduction - physiology

Mitochondria - metabolism

Retinal Ganglion Cells - metabolism

A Kinase Anchor Proteins - metabolism

Mitochondrial Dynamics - physiology

Details

Title: Subtitle: Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells
Creators: Genea Edwards - Hamilton Glaucoma Center and Shiley Eye Center, The Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
Guy A Perkins - National Center for Microscopy and Imaging Research and Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Keun-Young Kim - National Center for Microscopy and Imaging Research and Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
YeEun Kong - Hamilton Glaucoma Center and Shiley Eye Center, The Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
Yonghoon Lee - Hamilton Glaucoma Center and Shiley Eye Center, The Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
Soo-Ho Choi - Department of Medicine, University of California San Diego, La Jolla, CA, USA
Yujia Liu - Department of Pharmacology and Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
Dorota Skowronska-Krawczyk - Hamilton Glaucoma Center and Shiley Eye Center, The Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
Robert N Weinreb - Hamilton Glaucoma Center and Shiley Eye Center, The Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
Linda Zangwill - Hamilton Glaucoma Center and Shiley Eye Center, The Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
Stefan Strack - Department of Pharmacology and Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
Won-Kyu Ju - Hamilton Glaucoma Center and Shiley Eye Center, The Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA. wju@ucsd.edu
Resource Type: Journal article
Publication Details: Cell death & disease, Vol.11(4), pp.254-254
DOI: 10.1038/s41419-020-2456-6
PMID: 32312949
PMCID: PMC7170863
NLM abbreviation: Cell Death Dis
ISSN: 2041-4889
eISSN: 2041-4889
Publisher: England
Grant note: P41 GM103412 / NIGMS NIH HHS P30 EY022589 / NEI NIH HHS T32 EY026590 / NEI NIH HHS R24 GM137200 / NIGMS NIH HHS R01 EY018658 / NEI NIH HHS R01 EY027011 / NEI NIH HHS
Language: English
Date published: 04/20/2020
Academic Unit: Pathology; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
Record Identifier: 9984071695402771

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