Intramitochondrial Zn2+ accumulation via the Ca2+ uniporter contributes to acute ischemic neurodegeneration

Abstract

Ca2+ and Zn2+ have both been implicated in the induction of acute ischemic neurodegeneration. We recently examined changes in intracellular Zn2+ and Ca2+ in CA1 pyramidal neurons subjected to oxygen glucose deprivation (OGD), and found that Zn2+ rises precede and contribute to the onset of terminal Ca2+ rises (“Ca2+ deregulation”), which are causatively linked to a lethal loss of membrane integrity. The present study seeks to examine the specific role of intramitochondrial Zn2+ accumulation in ischemic injury, using blockers of the mitochondrial Ca2+ uniporter (MCU), through which both Zn2+ and Ca2+ appear able to enter the mitochondrial matrix. In physiological extracellular Ca2+, treatment with the MCU blocker, Ruthenium Red (RR), accelerated the Ca2+ deregulation, most likely by disrupting mitochondrial Ca2+ buffering and thus accelerating the lethal cytosolic Ca2+ overload. However, when intracellular Ca2+ overload was slowed, either by adding blockers of major Ca2+ entry channels or by lowering the concentration of Ca2+ in the extracellular buffer, Ca2+ deregulation was delayed, and under these conditions either Zn2+ chelation or MCU blockade resulted in similar further delays of the Ca2+ deregulation. In parallel studies using the reactive oxygen species (ROS) indicator, hydroethidine, lowering Ca2+ surprisingly accelerated OGD induced ROS generation, and in these low Ca2+ conditions, either Zn2+ chelation or MCU block slowed the ROS generation. These studies suggest that, during acute ischemia, Zn2+ entry into mitochondria via the MCU induces mitochondrial dysfunction (including ROS generation) that occurs upstream of, and contributes to the terminal Ca2+ deregulation.

Cyanidin-3-glucoside inhibits glutamate-induced Zn2+ signaling and neuronal cell death in cultured rat hippocampal neurons by inhibiting Ca2+-induced mitochondrial depolarization and formation of reactive oxygen species

“…However, two antioxidants such as Trolox and DTT did not affect glutamate-induced mitochondrial depolarization as well as [Ca 2þ ] i increase. It has been suggest that early Zn 2þ entry into mitochondria through mitochondrial Ca 2þ uniporter contributes to mitochondrial dysfunction and formation of ROS during ischemia (Medvedeva and Weiss, 2014). All these data suggest that C3G inhibits glutamate-induced [Zn 2þ ] i increase by inhibiting formation of ROS through Ca 2þ -dependent mitochondrial depolarization, but not by ROS-dependent mitochondrial depolarization.…”

TRPV4 channels: physiological and pathological role in cardiovascular system

“…However, apart from TRPV4 blocking activity, ruthenium red also possesses the ability to block mitochondrial Ca 2? uniporter [52,94] and ryanodine receptors [68,105]. Accordingly, the cross reactivity of ruthenium red with other targets may possibly contribute to several experimental artifacts.…”

Reduction of zinc accumulation in mitochondria contributes to decreased cerebral ischemic injury by normobaric hyperoxia treatment in an experimental stroke model

“…These findings suggest a possible mechanism of NBO in protecting the penumbra, thus reducing cerebral ischemic injury in ischemic stroke rats. A Ca 2+ uniporter was reported to be involved in mediating zinc entry into mitochondria, which contributed to mitochondrial dysfunction in OGD treated neurons (Medvedeva & Weiss 2014). Further studies are needed to investigate how zinc accumulates in mitochondria during cerebral ischemia.…”