Title

Loss Of Opa1 Disturbs Cellular Calcium Homeostasis And Sensitizes For Excitotoxicity

Keywords

calcium; mitochondria; OPA1

Abstract

Optic atrophy 1 (OPA1) mutations cause dominant optic atrophy (DOA) with retinal ganglion cell (RGC) and optic nerve degeneration. The mechanism for the selective degeneration of RGCs in DOA remains elusive. To address the mechanism, we reduced OPA1 protein expression in cell lines and RGCs by RNA interference. OPA1 loss results in mitochondrial fragmentation, deficiency in oxidative phosphorylation, decreased ATP levels, decreased mitochondrial Ca 2+ retention capacity, reduced mtDNA copy numbers, and sensitization to apoptotic insults. We demonstrate profound cristae depletion and loss of crista junctions in OPA1 knockdown cells, whereas the remaining crista junctions preserve their normal size. OPA1-depleted cells exhibit decreased agonist-evoked mitochondrial Ca 2+ transients and corresponding reduction of NAD + to NADH, but the impairment in NADH oxidation leads to an overall more reduced mitochondrial NADH pool. Although in our model OPA1 loss in RGCs has no apparent impact on mitochondrial morphology, it decreases buffering of cytosolic Ca 2+ and sensitizes RGCs to excitotoxic injury. Exposure to glutamate triggers delayed calcium deregulation (DCD), often in a reversible manner, indicating partial resistance of RGCs to this injury. However, when OPA1 is depleted, DCD becomes irreversible. Thus, our data show that whereas OPA1 is required for mitochondrial fusion, maintenance of crista morphology and oxidative phosphorylation, loss of OPA1 also results in defective Ca 2+ homeostasis. © 2013 Macmillan Publishers Limited All rights reserved.

Publication Date

2-1-2013

Publication Title

Cell Death and Differentiation

Volume

20

Issue

2

Number of Pages

353-365

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1038/cdd.2012.128

Socpus ID

84872356908 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/84872356908

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