A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics

Abstract

Glutamate excitotoxicity leads to fragmented mitochondria in neurodegenerative diseases, mediated by nitric oxide and S-nitrosylation of dynamin-related protein 1, a mitochondrial outer membrane fission protein. Optic atrophy gene 1 (OPA1) is an inner membrane protein important for mitochondrial fusion. Autosomal dominant optic atrophy (ADOA), caused by mutations in OPA1, is a neurodegenerative disease affecting mainly retinal ganglion cells (RGCs). Here, we showed that OPA1 deficiency in an ADOA model influences N-methyl-D-aspartate (NMDA) receptor expression, which is involved in glutamate excitotoxicity and oxidative stress. Opa1enu/+ mice show a slow progressive loss of RGCs, activation of astroglia and microglia, and pronounced mitochondrial fission in optic nerve heads as found by electron tomography. Expression of NMDA receptors (NR1, 2A, and 2B) in the retina of Opa1enu/+ mice was significantly increased as determined by western blot and immunohistochemistry. Superoxide dismutase 2 (SOD2) expression was significantly decreased, the apoptotic pathway was activated as Bax was increased, and phosphorylated Bad and BcL-xL were decreased. Our results conclusively demonstrate that not only glutamate excitotoxicity and/or oxidative stress alters mitochondrial fission/fusion, but that an imbalance in mitochondrial fission/fusion in turn leads to NMDA receptor upregulation and oxidative stress. Therefore, we propose a new vicious cycle involved in neurodegeneration that includes glutamate excitotoxicity, oxidative stress, and mitochondrial dynamics.

Inhibition of N-Methyl-d-aspartate-induced Retinal Neuronal Death by Polyarginine Peptides Is Linked to the Attenuation of Stress-induced Hyperpolarization of the Inner Mitochondrial Membrane Potential

“…Glutamate-induced oxidative stress and retinal ischemia promote mitochondrial dysfunction (66,67), and novel strategies eliciting prolonged mitochondrial stabilization, such as regimented C-R(7) treatment, may protect RGC function against glaucomatous damage (7). On a broader scale, therapeutic treatment with C-R(7) may have the potential to minimize mitochondrially induced damage resulting from stroke or traumatic brain injury (55,68) and possibly serve to ameliorate slow progressive neurodegenerative disorders such as multiple sclerosis and Parkinson disease (69).…”

Oxidative Stress and the Central Nervous System

“…Mechanisms by which ROS cause cerebral tissue damage are not well understood but ROS are reported to trigger a variety of molecular cascades that increase blood-brain barrier permeability and alter brain morphology, thus causing neuroinflammation, and neuronal death (Gu et al, 2011). Involvement of hypothalamic-pituitary-adrenal axis-mediated glucocorticoid receptor signaling, glutamate toxicity, and N-methyl-D-aspartate receptor signaling systems also has been suggested (Makino et al, 1996;Okamoto et al, 1999;Tanaka et al, 1999;Albrecht et al, 2010;Nguyen et al, 2011). Thus, evidence of increased brain oxidative damage in the development of central nervous system pathologies has been reported for neurodegenerative diseases, including Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis, cerebrovascular disorders, demyelinating diseases, and psychiatric disorders (Sorce and Krause, 2009).…”

Coenzyme Q10 Benefits Symptoms in Gulf War Veterans: Results of a Randomized Double-Blind Study

“…OS ↔ Mitochondrial dysfunction OS impairs mitochondrial function (Genova et al, 2004;Huet, Dupic, Harrois, & Duranteau, 2011;Wei, 1998). OS and glutamate excitotoxicity may affect mitochondrial fission-fusion (Nguyen et al, 2011) (altering mitochondrial "dynamics" and morphology) which in turn lead to up-regulation in NMDA (glutamate) receptors and OS (Nguyen et al, 2011). (SOD2 overexpression protects, implicating oxidative mechanisms (Nguyen et al, 2011).)…”

“…OS and glutamate excitotoxicity may affect mitochondrial fission-fusion (Nguyen et al, 2011) (altering mitochondrial "dynamics" and morphology) which in turn lead to up-regulation in NMDA (glutamate) receptors and OS (Nguyen et al, 2011). (SOD2 overexpression protects, implicating oxidative mechanisms (Nguyen et al, 2011).) Mitochondrial dysfunction increases OS (Genova et al, 2004;Wei, 1998).…”