Inhibition of mitochondrial function in astrocytes: implications for neuroprotection.

Abstract

Much evidence suggests that astrocytes protect neurons against ischemic injury. Although astrocytes are more resistant to some insults than neurons, few studies offer insight into the real time changes of astrocytic protective functions with stress. Mitochondria are one of the primary targets of ischemic injury in astrocytes. We investigated the time course of changes in astrocytic ATP levels, plasma membrane potential, and glutamate uptake, a key protective function, induced by mitochondrial inhibition. Our results show that significant functional change precedes reduction in astrocytic viability with mitochondrial inhibition. Using the mitochondrial inhibitor fluorocitrate (FC, 0.25 mmol/L) that is preferentially taken by astrocytes we found that inhibition of astrocyte mitochondria increased vulnerability of co-cultured neurons to glutamate toxicity. In our studies, the rates of FC-induced astrocytic mitochondrial depolarization were accelerated in mixed astrocyte/neuron cultures. We hypothesized that the more rapid mitochondrial depolarization was promoted by an additional energetic demand imposed be the co-cultured neurons. To test this hypothesis, we exposed pure astrocytic cultures to 0.01-1 mmol/L aspartate as a metabolic load. Aspartate application accelerated the rates of FC-induced mitochondrial depolarization, and, at 1 mmol/L, induced astrocytic death, suggesting that strong energetic demands during ischemia can compromise astrocytic function and viability.

• Authors: Ludmila A Voloboueva, Sang Won Suh, Raymond A Swanson, Rona G Giffard
• Journal: Journal of neurochemistry (J Neurochem) Vol. 102 Issue 4 Pg. 1383-94 (Aug 2007) ISSN: 0022-3042 [Print] England
• PMID: 17488276 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Citrates
• Neuroprotective Agents
• fluorocitrate
• Glutamic Acid
• Adenosine Triphosphate

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Animals, Newborn
• Astrocytes (drug effects, ultrastructure)
• Cell Death (drug effects, physiology)
• Cells, Cultured
• Cerebral Cortex (cytology)
• Citrates (pharmacology)
• Dose-Response Relationship, Drug
• Drug Interactions
• Glutamic Acid (pharmacology)
• Membrane Potential, Mitochondrial (drug effects, physiology)
• Membrane Potentials (drug effects, physiology)
• Mice
• Mitochondria (drug effects, physiology)
• Neurons (drug effects, physiology)
• Neuroprotective Agents (pharmacology)
• Time Factors