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Mitochondrial Calcium Transport and Mitochondrial Dysfunction After Global Brain Ischemia in Rat Hippocampus

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Abstract

Here we report effect of ischemia-reperfusion on mitochondrial Ca2+ uptake and activity of complexes I and IV in rat hippocampus. By performing 4-vessel occlusion model of global brain ischemia, we observed that 15 min ischemia led to significant decrease of mitochondrial capacity to accumulate Ca2+ to 80.8% of control whereas rate of Ca2+ uptake was not significantly changed. Reperfusion did not significantly change mitochondrial Ca2+ transport. Ischemia induced progressive inhibition of complex I, affecting final electron transfer to decylubiquinone. Minimal activity of complex I was observed 24 h after ischemia (63% of control). Inhibition of complex IV activity to 80.6% of control was observed 1 h after ischemia. To explain the discrepancy between impact of ischemia on rate of Ca2+ uptake and activities of both complexes, we performed titration experiments to study relationship between inhibition of particular complex and generation of mitochondrial transmembrane potential (ΔΨm). Generation of a threshold curves showed that complex I and IV activities must be decreased by approximately 40, and 60%, respectively, before significant decline in ΔΨm was documented. Thus, mitochondrial Ca2+ uptake was not significantly affected by ischemia-reperfusion, apparently due to excess capacity of the complexes I and IV. Inhibition of complex I is favourable of reactive oxygen species (ROS) generation. Maximal oxidative modification of membrane proteins was documented 1 h after ischemia. Although enhanced formation of ROS might contribute to neuronal injury, depressed activities of complex I and IV together with unaltered rate of Ca2+ uptake are conditions favourable of initiation of other cell degenerative pathways like opening of mitochondrial permeability transition pore or apoptosis initiation, and might represent important mechanism of ischemic damage to neurones.

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Acknowledgments

This work was supported by the Ministry of Education of Slovak Republic (grants VEGA 1/4255/07 and VVCE 0064-07). Authors are grateful to Zdenka Cetlova for her excellent technical assistance.

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  1. Institute of Biochemistry, Jessenius Faculty of Medicine, Comenius University, Mala Hora 4, 03601, Martin, Slovak Republic

    Peter Racay, Zuzana Tatarkova, Maria Chomova, Jozef Hatok, Peter Kaplan & Dusan Dobrota

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  1. Peter Racay
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  2. Zuzana Tatarkova
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  3. Maria Chomova
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  4. Jozef Hatok
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Correspondence to Peter Racay.

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Racay, P., Tatarkova, Z., Chomova, M. et al. Mitochondrial Calcium Transport and Mitochondrial Dysfunction After Global Brain Ischemia in Rat Hippocampus. Neurochem Res 34, 1469–1478 (2009). https://doi.org/10.1007/s11064-009-9934-7

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