Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury

Abstract

Glaucoma is the most substantial cause of irreversible blinding, which is accompanied by progressive retinal ganglion cell damage. Retinal ganglion cells are energy-intensive neurons that connect the brain and retina, and depend on mitochondrial homeostasis to transduce visual information through the brain. As cofactors that regulate many metabolic signals, iron and zinc have attracted increasing attention in studies on neurons and neurodegenerative diseases. Here, we summarize the research connecting iron, zinc, neuronal mitochondria, and glaucomatous injury, with the aim of updating and expanding the current view of how retinal ganglion cells degenerate in glaucoma, which can reveal novel potential targets for neuroprotection.

Increased Mobile Zinc Regulates Retinal Ganglion Cell Survival via Activating Mitochondrial OMA1 and Integrated Stress Response

“…It is known that both Zn 2+ and mitochondrial dysfunction contribute to progressive RGC loss following optic nerve injury [ 11 ]. The mitochondrial zinc metalloprotease OMA1 senses mitochondrial stress and regulates mitochondrial homeostasis [ 43 ].…”

“…Mitochondria are involved in various biological processes, such as energy metabolism, signaling, reactive oxygen species (ROS) production, Ca 2+ regulation, anti-pathogenic mechanisms, and programmed cell death (e.g., apoptosis and ferroptosis) [ 7 , 8 , 9 , 10 ]. Recent evidence has suggested mitochondrial vulnerability, such as NAD + decline, mitochondrial fission increase, and mitochondrial unfolded protein response, as an emerging hypothesis for the pathogenesis of RGC injury [ 11 , 12 ]. Some mitochondria-targeted treatments (e.g., vitamin B3) have been shown to offer RGC protection in animal models and clinical trials [ 12 , 13 ].…”

“…Under various stimuli, cytosolic zinc metalloproteins liberate zinc and increase the intracellular Zn 2+ level. The cellular Zn 2+ could: (1) form a cytosolic labile zinc pool and mediate ROS generation; (2) move into the mitochondria and other subcellular compartments (e.g., endoplasmic reticulum); and (3) be transported to the postsynaptic neurons by synaptic vesicles [ 11 ]. Notably, Zn 2+ overload of mitochondria leads to mitochondrial depolarization, excessive fission, and increased permeability, resulting in neuronal death [ 15 , 16 , 17 , 18 ].…”

Crosstalk of copper and zinc in the pathogenesis of vascular dementia

“…(71) Moreover, Zn has been reported to inhibit various mitochondrial enzymes, such as mitochondrial complex I, aconitase, cytochrome c oxidase, α-ketoglutarate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, and monoamine oxidase. (72) Thus, the energy failure pathway in mitochondria is suggested to be involved in the process of Zn-induced neurotoxicity.…”

“…We demonstrated that the admin­istration of sodium pyruvate, an energy substrate, significantly inhibited Zn-induced death in GT1-7 cells.‍ ( 66 ) Sheline et al ‍ ( 70 ) reported that Zn exposure decreased the levels of NAD‍ + and ATP in cultured cortical neurons and that treatment with pyruvate restored the NAD‍ + level. Administration of pyruvate attenuated neuronal death after ischemia also in vivo .‍ ( 71 ) Moreover, Zn has been reported to inhibit various mitochondrial enzymes, such as mitochondrial complex I, aconitase, cytochrome c oxidase, α-ketoglutarate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, and monoamine oxidase.‍ ( 72 ) Thus, the energy failure pathway in mitochondria is suggested to be involved in the process of Zn-induced neurotoxicity.…”