Blocking Mitochondrial Zn Accumulation after Ischemia Reduces Mitochondrial Dysfunction and Neuronal Injury.

Zn is an important contributor to ischemic brain injury, and recent studies support the hypothesis that mitochondria are key sites of its injurious effects. In murine hippocampal slices (both sexes) subjected to oxygen glucose deprivation (OGD), we found that Zn accumulation and its entry into mitochondria precedes and contributes to the induction of acute neuronal death. In addition, if the ischemic episode is short (and sublethal), there is ongoing Zn accumulation in CA1 mitochondria after OGD that may contribute to their delayed dysfunction.

Zn entry through the mitochondrial calcium uniporter is a critical contributor to mitochondrial dysfunction and neurodegeneration.

Excitotoxic Ca accumulation contributes to ischemic neurodegeneration, and Ca can enter the mitochondria through the mitochondrial calcium uniporter (MCU) to promote mitochondrial dysfunction. Yet, Ca-targeted therapies have met limited success. A growing body of evidence has highlighted the underappreciated importance of Zn, which also accumulates in neurons after ischemia and can induce mitochondrial dysfunction and cell death.

Rapid Intramitochondrial Zn2+ Accumulation in CA1 Hippocampal Pyramidal Neurons After Transient Global Ischemia: A Possible Contributor to Mitochondrial Disruption and Cell Death.

Mitochondrial Zn2+ accumulation, particularly in CA1 neurons, occurs after ischemia and likely contributes to mitochondrial dysfunction and subsequent neurodegeneration. However, the relationship between mitochondrial Zn2+ accumulation and their disruption has not been examined at the ultrastructural level in vivo. We employed a cardiac arrest model of transient global ischemia (TGI), combined with Timm's sulfide silver labeling, which inserts electron dense metallic silver granules at sites of labile Zn2+ accumulation, and used transmission electron microscopy (TEM) to examine subcellular loci of the Zn2+ accumulation.

Intracellular calcium dysregulation in autism spectrum disorder: An analysis of converging organelle signaling pathways.

Autism spectrum disorder (ASD) is a group of complex, neurological disorders that affect early cognitive, social, and verbal development. Our understanding of ASD has vastly improved with advances in genomic sequencing technology and genetic models that have identified >800 loci with variants that increase susceptibility to ASD. Although these findings have confirmed its high heritability, the underlying mechanisms by which these genes produce the ASD phenotypes have not been defined.

Mitochondrial Zn Accumulation: A Potential Trigger of Hippocampal Ischemic Injury.

Ischemic stroke is a major cause of death and disabilities worldwide, and it has been long hoped that improved understanding of relevant injury mechanisms would yield targeted neuroprotective therapies. While Ca overload during ischemia-induced glutamate excitotoxicity has been identified as a major contributor, failures of glutamate targeted therapies to achieve desired clinical efficacy have dampened early hopes for the development of new treatments. However, additional studies examining possible contributions of Zn, a highly prevalent cation in the brain, have provided new insights that may help to rekindle the enthusiasm.

Differential Vulnerability of CA1 versus CA3 Pyramidal Neurons After Ischemia: Possible Relationship to Sources of Zn2+ Accumulation and Its Entry into and Prolonged Effects on Mitochondria.

Unlabelled: Excitotoxic mechanisms contribute to the degeneration of hippocampal pyramidal neurons after recurrent seizures and brain ischemia. However, susceptibility differs, with CA1 neurons degenerating preferentially after global ischemia and CA3 neurons after limbic seizures. Whereas most studies address contributions of excitotoxic Ca entry, it is apparent that Zn also contributes, reflecting accumulation in neurons either after synaptic release and entry through postsynaptic channels or upon mobilization from intracellular Zn-binding proteins such as metallothionein-III (MT-III).

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.

Mitochondria and plasma membrane Ca2+-ATPase control presynaptic Ca2+ clearance in capsaicin-sensitive rat sensory neurons.

The central processes of primary nociceptors form synaptic connections with the second-order nociceptive neurons located in the dorsal horn of the spinal cord. These synapses gate the flow of nociceptive information from the periphery to the CNS, and plasticity at these synapses contributes to centrally mediated hyperalgesia and allodynia. Although exocytosis and synaptic plasticity are controlled by Ca(2+) at the release sites, the mechanisms underlying presynaptic Ca(2+) signalling at the nociceptive synapses are not well characterized.

Sensitive and selective detection of zinc ions in neuronal vesicles using PYDPY1, a simple turn-on dipyrrin.

A new class of in vitro Zn(II) chemosensor based on dipyrrin has been developed. 5-(Pyren-1-yl)-4,6-dipyrrin (PYDPY1) was synthesized and exhibited high selectivity and sensitivity to Zn(II) (K(d) of 20 μM) compared to other metal ions. PYDPY1 was applied to the visualization of Zn(II) concentration in hippocampal tissue.

Intracellular Zn2+ accumulation contributes to synaptic failure, mitochondrial depolarization, and cell death in an acute slice oxygen-glucose deprivation model of ischemia.

Despite considerable evidence for contributions of both Zn(2+) and Ca(2+) in ischemic brain damage, the relative importance of each cation to very early events in injury cascades is not well known. We examined Ca(2+) and Zn(2+) dynamics in hippocampal slices subjected to oxygen-glucose deprivation (OGD). When single CA1 pyramidal neurons were loaded via a patch pipette with a Ca(2+)-sensitive indicator (fura-6F) and an ion-insensitive indicator (AlexaFluor-488), small dendritic fura-6F signals were noted after several (approximately 6-8) minutes of OGD, followed shortly by sharp somatic signals, which were attributed to Ca(2+) ("Ca(2+) deregulation").

AKAP150-anchored PKA activity is important for LTD during its induction phase.

Protein kinase A (PKA) is thought to tonically maintain an enhanced level of postsynaptic AMPA receptor responses. Injection of PKA inhibitory peptides leads to a run-down of AMPA receptor responses and prevents long-term depression (LTD). This run-down of AMPA receptor activity was proposed to occlude a further reduction that would otherwise constitute LTD.

Mechanisms of prolonged presynaptic Ca2+ signaling and glutamate release induced by TRPV1 activation in rat sensory neurons.

Transient receptor potential vanilloid receptor 1 (TRPV1)-mediated release of neuroactive peptides and neurotransmitters from the peripheral and central terminals of primary sensory neurons can critically contribute to nociceptive processing at the periphery and in the CNS. However, the mechanisms that link TRPV1 activation with Ca2+ signaling at the release sites and neurosecretion are poorly understood. Here we demonstrate that a brief stimulation of the receptor using either capsaicin or the endogenous TRPV1 agonist N-arachidonoyl-dopamine induces a prolonged elevation of presynaptic [Ca2+](i) and a concomitant enhancement of glutamate release at sensory synapses.