The role of lysosomes in iron metabolism and recycling

Abstract

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

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

“…40 Iron availability thus appears critical in influencing HTC death, strongly supporting the notion that it plays a central role in TNF and CHX toxicity. Low-mass iron is physiologically available in lysosomes, mainly deriving from the breakdown of autophagocytosed ferruginous materials, 25,41 such as ferritin and mitochondria that carry the major share of intracellular iron. 42 Upon degradation of the protein backbone, bound iron is freed in the lysosomal lumen and kept in ferrous (Fe 2+ ) form by the low pH and the reducing environment of lysosomes.…”

Lysosomes in programmed cell death pathways: from initiators to amplifiers

“…Alternatively, O 2˙− presence leads to reduction of iron and occurrence of harmful hydroxyl radical OH˙. Further, the ferric cation Fe 3+ formed in the Fenton reaction can react with the superoxide anion in the so-called Haber-Weiss reaction, generating ferrous iron again (Fe 3+ + O2˙− → Fe 2+ + O 2 ), which can re-enter into the Fenton reaction (Kurz et al, 2007;Kurz et al, 2011;Dixon et al, 2012). Depending on the extent of highly reactive HO .…”

“…It was suggested that ROS initiate also activation of phospholipase A2 (PLA2) and lysosomal Ca 2+ channels. PLA2 may affect trafficking of K + and H + ions and lysosomal membrane integrity by the production of arachidonic acid, which exhibits detergent-like properties (Kurz et al, 2011;Cesen et al, 2012;Aits and Jaattela, 2013).…”

“…Additionally, some studies have revealed that some metals like aluminum, zinc, copper and iron are trapped within lipofuscin. Among them iron has a special role as it is predominantly responsible for oxidation linked with the Fenton-type reactions, indicating that lysosomes are also involved in iron homeostasis (Kurz et al, 2007;Kurz et al, 2011;Hohn and Grune, 2013;Karlsson et al, 2013;Repnik et al, 2014;Bogdan et al, 2016). However, lysosomes are not associated only with the catabolic functions, but also with other processes, including cell death, inflammasome activation and immune response, as well as with lysosomal secretion and cholesterol recycling (Appelqvist et al, 2013;Mrschtik and Ryan, 2015).…”

“…However, lysosomes are not associated only with the catabolic functions, but also with other processes, including cell death, inflammasome activation and immune response, as well as with lysosomal secretion and cholesterol recycling (Appelqvist et al, 2013;Mrschtik and Ryan, 2015). As a consequence, disturbances in lysosomal functions are associated with numerous human diseases, such as cancer, neurodegenerative disorders, lysosomal storage diseases, cardiovascular disorders and many inflammation-associated diseases (Eskelinen and Saftig, 2009;Kurz et al, 2011;Appelqvist et al, 2013;Settembre et al, 2013;Jiang and Mizushima, 2014;Hu et al, 2015;Parenti et al, 2015;Bogdan et al, 2016;Stoka et al, 2016).…”