Mitochondrial Depolarization in Glutamate-Stimulated Neurons: An Early Signal Specific to Excitotoxin Exposure

Abstract

A brief exposure to high concentrations of glutamate kills cultured forebrain neurons by an excitotoxic process that is dependent on Ca2+ influx through the NMDA receptor. In this study, we have measured striking changes in mitochondrial function during and immediately after intense glutamate receptor activation. Using indo-1 microfluorometry and a specific inhibitor of the mitochondrial Na+/Ca2+ exchanger, CGP-37157, we have demonstrated that mitochondria accumulate large quantities of Ca2+ during a toxic glutamate stimulus and further that Ca2+ efflux from mitochondria contributes to the prolonged [Ca2+]i elevation after glutamate removal. We then used JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine+ ++ iodide), a ratiometric indicator of mitochondrial membrane potential (delta psi), to show that Ca2+ accumulation within the organelle dissipates delta psi. The abrupt loss of delta psi after glutamate stimulation did not occur in the presence of MK801 or in the absence of extracellular Ca2+. The mitochondrial depolarization was also cyclosporin A-sensitive, indicating a probable role for the permeability transition pore. Hence mitochondrial Ca2+ accumulation and the subsequent permeability transition may be a critical early event specific to the NMDA receptor-mediated excitotoxic cascade.

Mechanisms of Cell Death Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Acute Excitotoxic Necrosis and Delayed Apoptosis

“…Second, calcium and sodium influx may stimulate the consumption of ATP through Ca 2ϩ -ATPase and Na ϩ /K ϩ -ATPase. Moreover, calcium overload will ultimately disrupt mitochondrial function (Mattson et al, 1993;Medrano and Fox, 1994;Minezaki et al, 1994;Schinder et al, 1996;White and Reynolds, 1996). Cycloheximide has no effect on 3-NP-induced decline in cellular ATP levels, suggesting that loss of ATP is indeed an initial event and that cycloheximide acts downstream to ATP loss.…”

Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research

“…37 Additionally, recent research has confirmed that mitochondrial dysfunction plays a central role in ischemic injury, especially in cases of reperfusion following cerebral ischemia. [38][39][40][41][42][43][44] Consequently, findings of decreased pHi in bipolar subjects compared to normal controls suggest that impaired mitochondrial function may be an integral component of bipolar illness.…”

Cellular and Molecular Pathways of Ischemic Neuronal Death

“…Its driving force is generated by the negative membrane potential, ∆ψ m (Gunter and Gunter, 1994). Second, mitochondria become depolarized, due to the transport of Ca 2+ into the matrix and the inhibition of the oxidative phosphorylation (White and Reynolds, 1996;Ward et al, 2000;Rego et al, 2000). Third, inhibiting the mitochondrial Ca 2+ uptake reduces the Ca 2+ -mediated glutamate neurotoxicity (Stout et al, 1998).…”