Abstract
Mitochondrial dynamics have been extensively studied in the context of classical cell death models involving Bax-mediated cytochrome c release. Excitotoxic neuronal loss is a non-classical death signaling pathway that occurs following overactivation of glutamate receptors independent of Bax activation. Presently, the role of mitochondrial dynamics in the regulation of excitotoxicity remains largely unknown. Here, we report that NMDA-induced excitotoxicity results in defects in mitochondrial morphology as evident by the presence of excessive fragmented mitochondria, cessation of mitochondrial fusion, and cristae dilation. Up-regulation of the mitochondrial inner membrane GTPase, Opa1, is able to restore mitochondrial morphology and protect neurons against excitotoxic injury. Opa1 functions downstream of the calcium-dependent protease, calpain. Inhibition of calpain activity by calpastatin, an endogenous calpain inhibitor, significantly rescued mitochondrial defects and maintained neuronal survival. Opa1 was required for calpastatin-mediated neuroprotection because the enhanced survival found following NMDA-induced toxicity was significantly reduced upon loss of Opa1. Our results define a mechanism whereby breakdown of the mitochondrial network mediated through loss of Opa1 function contributes to neuronal death following excitotoxic neuronal injury. These studies suggest Opa1 as a potential therapeutic target to promote neuronal survival following acute brain damage and neurodegenerative diseases.
Highlights
Trauma, and is implicated in neurodegenerative diseases, such as Parkinson, Huntington, and Alzheimer diseases
Mitochondrial Morphology Defects following Excitotoxic Injury—Excitotoxicity is a key mechanism of cell death following acute neuronal injury that involves deregulation of intracellular calcium
At 7 day in vitro (DIV), neurons were treated with NMDA or DMSO control. 7– 8 h following treatment, the GFP signal was activated in a small region aimed at 2– 4 mitochondria (Fig. 2, A and B)
Summary
Trauma, and is implicated in neurodegenerative diseases, such as Parkinson, Huntington, and Alzheimer diseases (reviewed in Refs. 1 and 2). Optic atrophy 1 (Opa1) and mitofusins (Mfn1/2) regulate mitochondrial fusion, and dynamin-related protein 1 (Drp1) regulates mitochondrial fission (reviewed in Ref. 4). Because much of the function of mitochondria in cell death has focused on Baxmediated model systems (reviewed in Ref. 17), the role of mitochondrial dynamics in nonclassical death signaling pathways, such as excitotoxicity, remains largely unknown. Our study provides a new mechanistic link between components of inner mitochondrial membrane fusion and death signaling following excitotoxic neuronal injury. These dynamin GTPases may serve as key molecular targets by which to preserve neuronal survival after acute brain damage
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
