Autophagy of HSP70 and chelation of lysosomal iron in a non-redox-active form

Kurz, Tino; Brunk, Ulf T.

doi:10.4161/auto.5.1.7248

Cited by 44 publications

(35 citation statements)

References 28 publications

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“…31,32) Recently, cytoprotective functions of HSPs, particularly HSP70, have been connected to MAPKs signaling pathway. 33,34) For this reason, we investigated whether there is involvement of MAPKs in the induction of HSP70 by Z-ligustilide. As a result, phosphorylation of the three MAPKs was significantly influenced by Z-ligustilide.…”

Section: Discussionmentioning

confidence: 99%

Protective HSP70 Induction by Z-Ligustilide against Oxygen–Glucose Deprivation Injury <i>via</i> Activation of the MAPK Pathway but Not of HSF1

Jiang

Ning

et al. 2015

Biological & Pharmaceutical Bulletin

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Key words Z-ligustilide; heat-shock protein 70; mitogen-activated protein kinase; oxygen-glucose deprivation-reoxygenation; heat-shock factor 1The World Health Organization (WHO) Global Infobase reports that stroke has become the second leading cause of mortality in the world, causing around 6000000 deaths annually. 1)However, there are currently relatively few treatment options available to minimize damage or death following a stroke. Protein aggregates containing ubiquitinated proteins are commonly present in neurodegenerative disorders and have been considered to cause neuronal degeneration. The previous study also showed that transient cerebral ischemia caused severe protein aggregation in hippocampal CA1 neurons which appeared at 4 h and progressively accumulated at 24 and 48 h. 2)Therefore, control of protein aggregation may represent an alternative treatment to neurological damage caused by ischemic stroke.Heat shock proteins (HSPs) are a group of phylogenetically and ubiquitous cytoprotective proteins found in all prokaryotic and eukaryotic cells, many of which are chaperone molecules that facilitate protein folding, trafficking and also prevent their aggregation and degradation.3) Heat shock protein 70 (HSP70) is a major inducible heat shock protein that basically functions as a molecular chaperone and plays an important role in preventing protein aggregation, degrading unstable and misfolded proteins and transporting proteins between cellular compartments.4) It's reported that over-expression of HSP70 via transgenes and viruses or systemic administration of HSP70 fusion proteins that allow it to cross the blood brain barrier protects the brain against ischemia, 5,6) suggesting that increasing HSP70 level or activity may be a potential therapeutic target for pharmacological intervention of ischemic diseases.Ligusticum chuanxiong is a commonly used Chinese herbal medicine with its empiric treatment of cardiovascular and cerebrovascular diseases.7) Z-Ligustilide as the major bioactive phthalide compound of Rhizoma chuanxiong was previously suggested for the prevention and treatment of ischemic stroke. 8,9) Our and others' studies showed that Z-ligustilide could protect ischemic injury both in vitro and in vivo via the induction of direct and indirect antioxidant response. 8,10,11) However, its effect on the heat shock response, a highly conserved and fundamental cytoprotective mechanism, under ischemic stress remains unexplored. Along this line, we characterized the effect of Z-ligustilide on HSP70 and explored the potential role of HSP70 in the protection of Z-ligustilide against oxygen-glucose deprivation and reoxygenation (OGDReoxy) induced injury in this study.

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Section: Discussionmentioning

confidence: 99%

Protective HSP70 Induction by Z-Ligustilide against Oxygen–Glucose Deprivation Injury <i>via</i> Activation of the MAPK Pathway but Not of HSF1

Jiang

Ning

et al. 2015

Biological & Pharmaceutical Bulletin

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“…The cytosol contains a range of iron-binding proteins, such as metallothioneins, Hsp70 and ferritin (Baird et al, 2006, Kurz and Brunk, 2009, Kurz et al, 2011. These can all be autophagocytosed and then are able to bind lysosomal redox-active iron for a limited period of time until they are degraded.…”

Section: The Role Of Lysosomes In Intracellular Iron Metabolismmentioning

confidence: 99%

The role of lysosomes in iron metabolism and recycling

Kurz

Eaton

Brunk

2011

The International Journal of Biochemistry & Cell Biology

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172

134

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Iron is the most abundant transition metal in the earths crust. It cycles easily between ferric (oxidized; Fe(III)) and ferrous (reduced; Fe(II)) and readily forms complexes with oxygen, making this metal a central player in respiration and related redox processes. However, loose iron, not within heme or iron-sulfur cluster proteins, can be destructively redox-active, causing damage to almost all cellular components, killing both cells and organisms. This may explain why iron is so carefully handled by aerobic organisms. Iron uptake from the environment is carefully limited and carried out by specialized iron transport mechanisms. One reason that iron uptake is tightly controlled is that most organisms and cells cannot efficiently excrete excess iron. When even small amounts of intracellular free iron occur, most of it is safely stored in a non-redox-active form in ferritins. Within nucleated cells, iron is constantly being recycled from aged iron-rich organelles such as mitochondria and used for construction of new organelles. Much of this recycling occurs within the lysosome, an acidic digestive organelle. Because of this, most lysosomes contain relatively large amounts of redox-active iron and are therefore unusually susceptible to oxidant-mediated destabilization or rupture. In many cell types, iron transit through the lysosomal compartment can be remarkably brisk. However, conditions adversely affecting lysosomal iron handling (or oxidant stress) can contribute to a variety of acute and chronic diseases. These considerations make normal and abnormal lysosomal handling of iron central to the understanding and, perhaps, therapy of a wide range of diseases

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“…The exact role of iron in the formation of autophagosomes is unclear; however, iron chelators do induce the formation of catabolic autophagosomes (45). Interestingly, since lysosomes contain most of the cellular supply of labile iron, iron binding proteins can be sequestered in autophagosomes as a strategy to minimize the damage from free iron (134). In some circumstances, iron chelators can prevent autophagy by sequestering the iron used in the formation of autophagosomes in response to H 2 O 2 (22,134).…”

Section: Cellular Responses To Dual Inhibitionmentioning

confidence: 99%

“…Interestingly, since lysosomes contain most of the cellular supply of labile iron, iron binding proteins can be sequestered in autophagosomes as a strategy to minimize the damage from free iron (134). In some circumstances, iron chelators can prevent autophagy by sequestering the iron used in the formation of autophagosomes in response to H 2 O 2 (22,134). Dp44mT can also cause autophagy, which is one pathway proposed to explain selective toxicity to cancer cells versus healthy cells (156,209).…”

Section: Cellular Responses To Dual Inhibitionmentioning

confidence: 99%

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Rao

2013

Antioxidants & Redox Signaling

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Significance: Iron and topoisomerases are abundant and essential cellular components. Iron is required for several key processes such as DNA synthesis, mitochondrial electron transport, synthesis of heme, and as a co-factor for many redox enzymes. Topoisomerases serve as critical enzymes that resolve topological problems during DNA synthesis, transcription, and repair. Neoplastic cells have higher uptake and utilization of iron, as well as elevated levels of topoisomerase family members. Separately, the chelation of iron and the cytotoxic inhibition of topoisomerase have yielded potent anticancer agents. Recent Advances: The chemotherapeutic drugs doxorubicin and dexrazoxane both chelate iron and target topoisomerase 2 alpha (top2a). Newer chelators such as di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone and thiosemicarbazone -24 have recently been identified as top2a inhibitors. The growing list of agents that appear to chelate iron and inhibit topoisomerases prompts the question of whether and how these two distinct mechanisms might interplay for a cytotoxic chemotherapeutic outcome. Critical Issues: While iron chelation and topoisomerase inhibition each represent mechanistically advantageous anticancer therapeutic strategies, dual targeting agents present an attractive multi-modal opportunity for enhanced anticancer tumor killing and overcoming drug resistance. The commonalities and caveats of dual inhibition are presented in this review. Future Directions: Gaps in knowledge, relevant biomarkers, and strategies for future in vivo studies with dual inhibitors are discussed. Antioxid. Redox Signal. 18, 930-955.

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Autophagy of HSP70 and chelation of lysosomal iron in a non-redox-active form

Cited by 44 publications

References 28 publications

Protective HSP70 Induction by Z-Ligustilide against Oxygen–Glucose Deprivation Injury <i>via</i> Activation of the MAPK Pathway but Not of HSF1

Protective HSP70 Induction by Z-Ligustilide against Oxygen–Glucose Deprivation Injury <i>via</i> Activation of the MAPK Pathway but Not of HSF1

The role of lysosomes in iron metabolism and recycling

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

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