Heterogeneity of the calcium-induced permeability transition in isolated non-synaptic brain mitochondria.
Calcium overload of neural cell mitochondria plays a key role in excitotoxic and ischemic brain injury. This study tested the hypothesis that brain mitochondria consist of subpopulations with differential sensitivity to calcium-induced inner membrane permeability transition, and that this sensitivity is greatly reduced by physiological levels of adenine nucleotides. Isolated non-synaptosomal rat brain mitochondria were incubated in a potassium-based medium in the absence or presence of ATP or ADP. Measurements were made of medium and intramitochondrial free calcium, light scattering, mitochondrial ultrastructure, and the elemental composition of electron-opaque deposits within mitochondria treated with calcium. In the absence of adenine nucleotides, calcium induced a partial decrease in light scattering, accompanied by three distinct ultrastructural morphologies, including large-amplitude swelling, matrix vacuolization and a normal appearance. In the presence of ATP or ADP the mitochondrial calcium uptake capacity was greatly enhanced and calcium induced an increase rather than a decrease in mitochondrial light scattering. Approximately 10% of the mitochondria appeared damaged and the rest contained electron-dense precipitates that contained calcium, as determined by electron-energy loss spectroscopy. These results indicate that brain mitochondria are heterogeneous in their response to calcium. In the absence of adenine nucleotides, approximately 20% of the mitochondrial population exhibit morphological alterations consistent with activation of the permeability transition, but less than 10% exhibit evidence of osmotic swelling and membrane disruption in the presence of ATP or ADP.
Kristián
Tibor
T
Department of Anesthesiology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, USA. Tkristian@anesthlab.umm.edu
Weatherby
Tina M
TM
Bates
Timothy E
TE
Fiskum
Gary
G
D000244:Adenosine Diphosphate / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001923:Brain Chemistry; D002118:Calcium / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004577:Electron Probe Microanalysis; D008027:Light; D008297:Male; D008928:Mitochondria / Q000737:chemistry* / Q000187:drug effects / Q000648:ultrastructure; D009994:Osmolar Concentration; D010539:Permeability / Q000187:drug effects; D011188:Potassium / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012542:Scattering, Radiation; D019802:Succinic Acid / Q000737:chemistry
D000244:Adenosine Diphosphate; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D019802:Succinic Acid; D011188:Potassium; D002118:Calcium