Abstract
Zinc dyshomeostasis has been recognized as an important mechanism for cell death in acute brain injury. An increase in the level of free or histochemically reactive zinc in astrocytes and neurons is considered one of the major causes of death of these cells in ischemia and trauma. Although zinc dyshomeostasis can lead to cell death via diverse routes, the major pathway appears to involve oxidative stress.Recently, we found that a rise of zinc in autophagic vacuoles, including autolysosomes, is a prerequisite for lysosomal membrane permeabilization and cell death in cultured brain cells exposed to oxidative stress conditions. The source of zinc in this process is likely redox-sensitive zinc-binding proteins such as metallothioneins, which release zinc under oxidative conditions. Of the metallothioneins, metallothionein-3 is especially enriched in the central nervous system, but its physiologic role in this tissue is not well established. Like other metallothioneins, metallothionein-3 may function as metal detoxicant, but is also known to inhibit neurite outgrowth and, sometimes, promote neuronal death, likely by serving as a source of toxic zinc release. In addition, metallothionein-3 regulates lysosomal functions. In the absence of metallothionein-3, there are changes in lysosome-associated membrane protein-1 and -2, and reductions in certain lysosomal enzymes that result in decreased autophagic flux. This may have dual effects on cell survival. In acute oxidative injury, zinc dyshomeostasis and lysosomal membrane permeabilization are diminished in metallothionein-3 null cells, resulting in less cell death. But over the longer term, diminished lysosomal function may lead to the accumulation of abnormal proteins and cause cytotoxicity.The roles of zinc and metallothionein-3 in autophagy and/or lysosomal function have just begun to be investigated. In light of evidence that autophagy and lysosomes may play significant roles in the pathogenesis of various neurological diseases, further insight into the contribution of zinc dynamics and metallothionein-3 function may help provide ways to effectively regulate these processes in brain cells.
Highlights
Cells have two major protein degradation pathways: the ubiquitin-proteasome system (UPS), which mainly acts to clear and recycle short-lived proteins [1], and macroautophagy or autophagy, in which lysosomal degradation is the final event [2]
Consistent with this, we found that cholesterol metabolism was altered and mutant huntingtin protein (mHttp) aggregates accumulated in the absence of metallothionein 3 (MT3) [31]
Recent studies have revealed that free zinc levels change in various organelles in response to physiologic or pathological stimuli, and suggest important functional consequences of these zinc dynamics
Summary
Cells have two major protein degradation pathways: the ubiquitin-proteasome system (UPS), which mainly acts to clear and recycle short-lived proteins [1], and macroautophagy or autophagy, in which lysosomal degradation is the final event [2]. In acute brain injury, the rise of intracellular free zinc levels contributes to neuronal and astrocytic cell death [37,66,67,68,69,70]. A recent surge in interest in autophagy has brought the lysosome to the fore as another organelle with a major role to play in cell death mechanisms In this context, the possibility that cellular free zinc may function as a link between oxidative stress and LMP is intriguing. The levels of autophagic markers such as LC3-II are markedly increased in astrocytes from MT3-null mice (Figure 1) Another interesting change induced by the absence of MT3 is a reduction in certain hydrolase activities that implies a decrease in lysosomal protein degradative capability. In neurodegenerative conditions in which the accumulation of protein aggregates contributes to the pathology, upregulation of MT3, and the associated enhancement in lysosomal function and protein degradation, may be beneficial (Figure 1)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
