Ferritin-stimulated lipid peroxidation, lysosomal leak, and macroautophagy promote lysosomal “metastability” in primary hepatocytes determining in vitro cell survival

Krenn, Margit; Schürz, Melanie; Teufl, Bernhard; Uchida, Koji; Eckl, Peter; Bresgen, Nikolaus

doi:10.1016/j.freeradbiomed.2014.12.007

Cited by 22 publications

(15 citation statements)

References 76 publications

(89 reference statements)

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“…Ferritin accumulation triggers macroautophagy which is abolished by Fe chelation, confirming the mechanistic role of Fe-induced ROS formation in the onset of ferritin toxicity. Also in this model, pharmacological inhibition of macroautophagy strongly enhanced ferritin toxicity, further substantiating the concept that induction of autophagy is a generalized defense mechanism against ROS-mediated cellular damage [ 140 ].…”

Section: Lysosomessupporting

confidence: 68%

Oxidative Stress in the Healthy and Wounded Hepatocyte: A Cellular Organelles Perspective

Mello

Zanieri

Ceni

et al. 2015

Oxidative Medicine and Cellular Longevity

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Accurate control of the cell redox state is mandatory for maintaining the structural integrity and physiological functions. This control is achieved both by a fine-tuned balance between prooxidant and anti-oxidant molecules and by spatial and temporal confinement of the oxidative species. The diverse cellular compartments each, although structurally and functionally related, actively maintain their own redox balance, which is necessary to fulfill specialized tasks. Many fundamental cellular processes such as insulin signaling, cell proliferation and differentiation and cell migration and adhesion, rely on localized changes in the redox state of signal transducers, which is mainly mediated by hydrogen peroxide (H2O2). Therefore, oxidative stress can also occur long before direct structural damage to cellular components, by disruption of the redox circuits that regulate the cellular organelles homeostasis. The hepatocyte is a systemic hub integrating the whole body metabolic demand, iron homeostasis and detoxification processes, all of which are redox-regulated processes. Imbalance of the hepatocyte's organelles redox homeostasis underlies virtually any liver disease and is a field of intense research activity. This review recapitulates the evolving concept of oxidative stress in the diverse cellular compartments, highlighting the principle mechanisms of oxidative stress occurring in the healthy and wounded hepatocyte.

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Section: Lysosomessupporting

confidence: 68%

Oxidative Stress in the Healthy and Wounded Hepatocyte: A Cellular Organelles Perspective

Mello

Zanieri

Ceni

et al. 2015

Oxidative Medicine and Cellular Longevity

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“…Therefore, when ROS levels are high, they can readily cross and damage the lysosomal membrane. Lysosomes are iron‐rich organelles that result from degradation of iron‐containing proteins, and free iron catalyzes the conversion of hydrogen peroxide into highly reactive hydroxyl radicals that can damage and destabilize lysosomal membranes . Iron chelation (eg, using desferrioxamine mesylate) can therefore protect against LDCD induced by oxidant challenge .…”

Section: Ldcd: Mechanism and Examplesmentioning

confidence: 99%

Lysosomal membrane permeabilization and cell death

Wang

Gómez‐Sintes

Boya

2018

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Lysosomes are membrane-enclosed organelles that mediate the intracellular degradation of macromolecules. They play an essential role in calcium regulation and have emerged as key signaling hubs in controlling the nutrient response. Maintaining lysosomal integrity and function is therefore crucial for cellular homeostasis. Different forms of stress can induce lysosomal membrane permeabilization (LMP), resulting in the translocation to the cytoplasm of intralysosomal components, such as cathepsins, inducing lysosomal-dependent cell death (LDCD). Here, we review recent advances that have furthered our understanding of the molecular mechanisms of LMP and the methods used to detect it. We discuss several endolysosomal damage-response mechanisms that mediate the repair or elimination of compromised lysosomes and summarize the role of LMP and cathepsins in LDCD and other cell death pathways. Finally, with the emergence of lysosomes as promising therapeutic targets for several human diseases, we review a variety of therapeutic strategies that seek to either destabilize lysosomes or to maintain, enhance or restore lysosomal function.

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“…It has been shown that autophagy of apoferritin protects lysosomes from iron overload and exerts cytoprotective properties [ 92 , 93 , 94 ]. On the other hand, ferritin heterophagy may stimulate lysosomal stress and resulting growth adverse responses [ 95 , 96 ].…”

Section: Cellular Iron Compartmentalizationmentioning

confidence: 99%

Oxidative Stress and the Homeodynamics of Iron Metabolism

2015

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Iron and oxygen share a delicate partnership since both are indispensable for survival, but if the partnership becomes inadequate, this may rapidly terminate life. Virtually all cell components are directly or indirectly affected by cellular iron metabolism, which represents a complex, redox-based machinery that is controlled by, and essential to, metabolic requirements. Under conditions of increased oxidative stress-i.e., enhanced formation of reactive oxygen species (ROS)-however, this machinery may turn into a potential threat, the continued requirement for iron promoting adverse reactions such as the iron/H2O2-based formation of hydroxyl radicals, which exacerbate the initial pro-oxidant condition. This review will discuss the multifaceted homeodynamics of cellular iron management under normal conditions as well as in the context of oxidative stress.Keywords: iron; oxidative stress; metabolism Systemic and Cellular Iron TransfersFerric iron or iron contained in heme is absorbed by intestinal enterocytes via heme carrier proteins (HCP1) [1], the divalent metal transporter DMT1 (SLC11A2) [2,3] or the integrin-mobilferrin pathway [4,5] (a review on intestinal iron absorption is given in [6,7]). The absorbed iron is then released from the enterocytes to the bloodstream as transferrin-bound iron (TBI) via ferroportin (see below). Under physiological conditions, the bulk of iron enters the cell bound as TBI via transferrin-receptor (TfR) mediated endocytosis followed by endosomal iron liberation. However, resorption of non-transferrin OPEN ACCESSBiomolecules 2015, 5 809 bound iron (NTBI) from the bloodstream may also occur either via DMT-1, the zinc transporter Zip14 (SLC39A14) [8,9] or specific citrate binding sites [10][11][12]. Notably, the serum content of labile NTBI is very low under normal conditions but may rise substantially in diseased states, such as thalassemia, where the high NTBI level-essentially caused by repeated blood transfusion-is considered to cause disease-related oxidative stress [13][14][15][16][17][18]. Similarly, serum ferritin which may serve as iron carrier too [19,20] and is also increased under certain pathological conditions, such as inflammation and cancer [21], can also be endocytosed [22][23][24][25] [34]. Finally, heme-bound iron will enter the cells via HCP1 [1] and tissue macrophages will also "ingest iron" upon phagocytosis of aged cells such as erythrocytes or via the haptoglobin/CD 163 or hemopexin/CD91 mediated uptake of hemoglobin or heme [35] and deliver the recycled iron back to the bloodstream, which is indispensable for the maintenance of systemic iron homeostasis [36].In contrast to several ways of cellular iron uptake, only two mechanisms of cellular iron release are known. Usually, iron release from a cell occurs via ferroportin (Fpn) [37][38][39][40][41] a membrane bound iron exporter, which is controlled by hepatocyte derived hepcidin [42,43], the hepcidin activity itself being regulated by the serine protease matriptase-2 [44,45]. The ferroportin-rel...

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Ferritin-stimulated lipid peroxidation, lysosomal leak, and macroautophagy promote lysosomal “metastability” in primary hepatocytes determining in vitro cell survival

Cited by 22 publications

References 76 publications

Oxidative Stress in the Healthy and Wounded Hepatocyte: A Cellular Organelles Perspective

Oxidative Stress in the Healthy and Wounded Hepatocyte: A Cellular Organelles Perspective

Lysosomal membrane permeabilization and cell death

Oxidative Stress and the Homeodynamics of Iron Metabolism

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