Intramitochondrial Zn2+ accumulation via the Ca2+ uniporter contributes to acute ischemic neurodegeneration.
Ca(2+) and Zn(2+) have both been implicated in the induction of acute ischemic neurodegeneration. We recently examined changes in intracellular Zn(2+) and Ca(2+) in CA1 pyramidal neurons subjected to oxygen glucose deprivation (OGD), and found that Zn(2+) rises precede and contribute to the onset of terminal Ca(2+) rises ("Ca(2+) deregulation"), which are causatively linked to a lethal loss of membrane integrity. The present study seeks to examine the specific role of intramitochondrial Zn(2+) accumulation in ischemic injury, using blockers of the mitochondrial Ca(2+) uniporter (MCU), through which both Zn(2+) and Ca(2+) appear able to enter the mitochondrial matrix. In physiological extracellular Ca(2+), treatment with the MCU blocker, Ruthenium Red (RR), accelerated the Ca(2+) deregulation, most likely by disrupting mitochondrial Ca(2+) buffering and thus accelerating the lethal cytosolic Ca(2+) overload. However, when intracellular Ca(2+) overload was slowed, either by adding blockers of major Ca(2+) entry channels or by lowering the concentration of Ca(2+) in the extracellular buffer, Ca(2+) deregulation was delayed, and under these conditions either Zn(2+) chelation or MCU blockade resulted in similar further delays of the Ca(2+) deregulation. In parallel studies using the reactive oxygen species (ROS) indicator, hydroethidine, lowering Ca(2+) surprisingly accelerated OGD induced ROS generation, and in these low Ca(2+) conditions, either Zn(2+) chelation or MCU block slowed the ROS generation. These studies suggest that, during acute ischemia, Zn(2+) entry into mitochondria via the MCU induces mitochondrial dysfunction (including ROS generation) that occurs upstream of, and contributes to the terminal Ca(2+) deregulation.
Department of Neurology, University of California, Irvine, Irvine, CA 92697, USA; Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: yvmedved@uci.edu.
Yuliya V
YV
Medvedeva
Department of Neurology, University of California, Irvine, Irvine, CA 92697, USA; Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: jweiss@uci.edu.
John H
JH
Weiss
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005029:Ethylenediamines / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000860:Hypoxia; D066298:In Vitro Techniques; D007202:Indicators and Reagents / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010617:Phenanthridines; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013997:Time Factors; D015032:Zinc / Q000378:metabolism*
D015220:Calcium Channels; D002614:Chelating Agents; D005029:Ethylenediamines; D018691:Excitatory Amino Acid Antagonists; D007202:Indicators and Reagents; D010617:Phenanthridines; D017382:Reactive Oxygen Species; C034703:mitochondrial calcium uniporter; C058428:hydroethidine; D005947:Glucose; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine; D002118:Calcium
Calcium; Hippocampal slice; Ischemia; Mitochondria; Mitochondrial Ca(2+) uniporter; ROS; RU360; Reactive oxygen species; Ruthenium Red; Zinc