Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6021954 | Neurobiology of Disease | 2014 | 8 Pages |
Abstract
Ca2Â + and Zn2Â + have both been implicated in the induction of acute ischemic neurodegeneration. We recently examined changes in intracellular Zn2Â + and Ca2Â + in CA1 pyramidal neurons subjected to oxygen glucose deprivation (OGD), and found that Zn2Â + rises precede and contribute to the onset of terminal Ca2Â + rises (“Ca2Â + deregulation”), which are causatively linked to a lethal loss of membrane integrity. The present study seeks to examine the specific role of intramitochondrial Zn2Â + accumulation in ischemic injury, using blockers of the mitochondrial Ca2Â + uniporter (MCU), through which both Zn2Â + and Ca2Â + appear able to enter the mitochondrial matrix. In physiological extracellular Ca2Â +, treatment with the MCU blocker, Ruthenium Red (RR), accelerated the Ca2Â + deregulation, most likely by disrupting mitochondrial Ca2Â + buffering and thus accelerating the lethal cytosolic Ca2Â + overload. However, when intracellular Ca2Â + overload was slowed, either by adding blockers of major Ca2Â + entry channels or by lowering the concentration of Ca2Â + in the extracellular buffer, Ca2Â + deregulation was delayed, and under these conditions either Zn2Â + chelation or MCU blockade resulted in similar further delays of the Ca2Â + deregulation. In parallel studies using the reactive oxygen species (ROS) indicator, hydroethidine, lowering Ca2Â + surprisingly accelerated OGD induced ROS generation, and in these low Ca2Â + conditions, either Zn2Â + chelation or MCU block slowed the ROS generation. These studies suggest that, during acute ischemia, Zn2Â + entry into mitochondria via the MCU induces mitochondrial dysfunction (including ROS generation) that occurs upstream of, and contributes to the terminal Ca2Â + deregulation.
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Authors
Yuliya V. Medvedeva, John H. Weiss,