Modulation of mitochondrial function by endogenous Zn ²⁺ pools

Abstract

Recent evidence suggests that intracellular Zn 2؉ accumulation contributes to the neuronal injury that occurs in epilepsy or ischemia in certain brain regions, including hippocampus, amygdala, and cortex. Although most attention has been given to the vesicular Zn 2؉ that is released into the synaptic space and may gain entry to postsynaptic neurons, recent studies have highlighted pools of intracellular Zn 2؉ that are mobilized in response to stimulation. One such Zn 2؉ pool is likely bound to cytosolic proteins, like metallothioneins. Applying imaging techniques to cultured cortical neurons, this study provides novel evidence for the presence of a mitochondrial pool distinct from the cytosolic protein or ligand-bound pool. These pools can be pharmacologically mobilized largely independently of each other, with Zn 2؉ release from one resulting in apparent net Zn 2؉ transfer to the other. Further studies found evidence for complex and potent effects of Zn 2؉ on isolated brain mitochondria. Submicromolar levels, comparable to those that might occur on strong mobilization of intracellular compartments, induced membrane depolarization (loss of ⌬ m), increases in currents across the mitochondrial inner membrane as detected by direct patch clamp recording of mitoplasts, increased O2 consumption and decreased reactive oxygen species (ROS) generation, whereas higher levels decreased O2 consumption and increased ROS generation. Finally, strong mobilization of proteinbound Zn 2؉ appeared to induce partial loss of ⌬ m, suggesting that movement of Zn 2؉ between cytosolic and mitochondrial pools might be of functional significance in intact neurons.

Intracellular zinc release-activated ERK-dependent GSK-3β–p53 and Noxa–Mcl-1 signaling are both involved in cardiac ischemic-reperfusion injury

“…At least two independent Zn 2 þ i pools were found to be located in the cytosolic and mitochondrial compartments, respectively, and the released Zn 2 þ translocated between the two compartments (Supplementary Figures S1c and d), as shown previously in neurons. 11 When TPEN was applied for only 20 min at the beginning of the 4-h reperfusion, there was a marked protective effect that lasted for at least 24 h (Figure 4b, Supplementary Figure S2b), suggesting that the initial Zn 2 þ (Figure 3b), is an important early death signal for the I/R injury seen at 24 h. When TPEN was applied throughout the 4-h reperfusion period, it provided more cardioprotection than other treatments, including GSK-3 inhibition, flavonoids, Ca 2 þ -free medium, CsA, or diazoxide (Figure 4b). TPEN also markedly abolished the Zn 2 þ i -dependent H 2 O 2 -or ONOO À -induced apoptosis.…”

“…Using time-lapse confocal microscopy of cardiomyocytes and two sensitive Zn 2 þ -selective probes FluoZin-3 AM (Kd ¼ 15 nM) and RhodZin3 AM (Kd ¼ 65 nM), 11 this study is the first to show that I/R, ROS, and RNS all cause significant cytosolic and/or mitochondrial Zn 2 þ i release. The role of altered zinc homeostasis in myocyte survival and the molecular mechanism involved was investigated.…”

Yeast Contain a Non-proteinaceous Pool of Copper in the Mitochondrial Matrix

“…The pool of zinc in mammalian mitochondria increases with increasing cytosolic zinc (55,56). Likewise, labile iron levels increase significantly within the mitochondria of yeast mutants defective in iron-sulfur cluster formation and processing (57,58).…”

Metal Ion availability in mitochondria

“…A mitochondrial Zn(II) pool was reported in neurons that can be pharmacologically mobilized during neuronal injury observed in cerebral ischemia (Sensi et al 2003). …”