The Mitochondrial Inner Membrane GTPase, Optic Atrophy 1 (Opa1), Restores Mitochondrial Morphology and Promotes Neuronal Survival following Excitotoxicity

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 nonclassical 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.

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…In this regard, decreased fission and fusion events due to an altered expression of the FIS1, DRP1 and MFN1 mRNAs after H 2 O 2 exposure were described (Jendrach et al, 2008). Accordingly, over-expression of proteins involved in mitochondrial fusion prevented mitochondrial fragmentation and cell death in cerebellar granule neurons treated with H 2 O 2 (Jahani- Asl et al, 2007;Jahani-Asl et al, 2011). The mitonetwork response to oxidative stress seemed to be dose-dependent, as higher concentrations or higher exposure times to H 2 O 2 increased the mitochondrial fragmentation extent and cell death rates Jahani-Asl et al, 2007;Jendrach et al, 2008).…”

Cellular Alterations in Human Traumatic Brain Injury: Changes in Mitochondrial Morphology Reflect Regional Levels of Injury Severity

“…Mitochondrial morphology and intracellular distribution are dependent on numerous factors, including mitochondrial energy state, changes in membrane permeability, physical interactions with the cytoskeleton, mitochondrial dynamics (movement, fission, fusion), and the balance between mitochondrial biogenesis and degradation. [4][5][6][7][8][9] Abnormalities in mitochondrial morphology accompany key events in the progression of excitotoxic neuronal injury 10 and are commonly observed in ischemic and traumatic brain injury (TBI) and in neurodegenerative disorders. [11][12][13] Patterns of mitochondrial ''morphodynamic'' changes may therefore be useful to monitor the alterations in the loss of cytoplasmic homeostasis and to provide insight into the subcellular pathophysiology of death.…”

Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity

“…31 Interestingly, the NMDA receptor inhibitor memantine is able to protect RGCs in glaucomatous retinas and prevent release of OPA1 from mitochondria. 51 Using cerebellar granule neurons, Jahani-Asl et al 52 showed that NMDA receptor overactivation triggers downstream Calpain activation, loss of OPA1 oligomers, deformation of crista junctions, and disruption of the respiratory chain complexes. Importantly, calpain activation is secondary to DCD.…”