The Function and Regulation of Zinc in the Brain

The Multifaceted Roles of Zinc in Neuronal Mitochondrial Dysfunction

“…Thus, investigating zinc and calcium in relation to one another may provide new insights into the mechanisms by which these ions work together to contribute to mitochondrial defects such as mitochondrial permeability transition. Excitingly, the development of various novel tools and methods for detecting cytosolic and mitochondrial zinc [ 260 ], as well as more selective and fast chelators [ 20 ], may allow us to investigate the effects of zinc on mitochondria with greater specificity and accuracy than ever before. Prior use of FluoZin-3 in tandem with the calcium indicator fura-2FF has been particularly useful for determining the simultaneous effects of zinc and calcium [ 189 , 190 , 261 ].…”

“…Most of the remaining labile, nominally unbound or weakly bound zinc in the brain is present in synaptic vesicles of a large population of excitatory glutamatergic neurons throughout the cerebral cortex, hippocampus, striatum, and auditory brainstem [ 10 , 11 , 12 ]. Zinc is concentrated within synaptic vesicles by zinc transporter 3 (ZnT3) [ 13 , 14 , 15 ] and is synaptically released in an activity-dependent manner, acting as a neuromodulator for a number of neurotransmitter receptors [ 16 , 17 , 18 , 19 , 20 ]. Additionally, zinc released at glutamatergic synapses can translocate into postsynaptic cells through calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs) [ 21 , 22 , 23 ], voltage-gated calcium channels (VGCCs) [ 24 , 25 ], and N-methyl-D-aspartate receptors (NMDARs) [ 26 ], subsequently activating a number of physiological and pathophysiological signaling processes [ 19 ].…”

Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter

“…For example, there are ion channels and transporters that localize to the plasma membrane or endo/sarcoplasmic reticulum, and even though they might conduct the same ions, they clearly have different impact on cellular function (Butorac et al, 2020; Gandini and Zamponi, 2021; Guse et al, 2021; Lemos et al, 2021; Lopez et al, 2020). Similarly, a large cohort of zinc transporters, responsible for pumping ionic zinc into distinct organelles or in or out of cells, subserve distinct functions, including synaptic modulation (Krall et al, 2021) and co-secretion with milk, in the latter case providing an essential dietary supplement and shaping mammary gland development (McCormick et al, 2014). The recent advances in genomic sequencing have resulted in identification of many putative transporters.…”

The Multifaceted Roles of Zinc in Neuronal Mitochondrial Dysfunction

“…Thus, investigating zinc and calcium in relation to one another may provide new insights into the mechanisms by which these ions work together to contribute to mitochondrial defects such as mitochondrial permeability transition. Excitingly, the development of various novel tools and methods for detecting cytosolic and mitochondrial zinc [255], as well as more selective and fast chelators [20] may allow us to investigate the effects of zinc on mitochondria with greater specificity and accuracy than ever before. Prior use of FluoZin-3 in tandem with the calcium indicator fura-2FF has been particularly useful for determining the simultaneous effects of zinc and calcium because FluoZin-3 is not sensitive to calcium [186,187,256].…”

“…Most of the remaining labile, nominally unbound or weakly bound zinc in the brain is present in synaptic vesicles of a large population of excitatory glutamatergic neurons throughout the cerebral cortex, hippocampus, striatum, and auditory brainstem [10][11][12]. Zinc is concentrated within synaptic vesicles by the zinc transporter 3 (ZnT3) [13][14][15] and is synaptically released in an activity-dependent manner, acting as a neuromodulator of a number of neurotransmitter receptors [16][17][18][19][20]. Additionally, zinc released at glutamatergic synapses can translocate into postsynaptic cells through calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs) [21][22][23], voltage-gated calcium channels (VGCCs) [24,25], and N-methyl-D-aspartate receptors (NMDARs) [26], subsequently activating a number of physiological and pathophysiological signaling processes [19].…”