The lysosome as a master regulator of iron metabolism

Intracellular iron fulfills crucial cellular processes, including DNA synthesis and mitochondrial metabolism, but also mediates ferroptosis, a regulated form of cell death driven by lipid-based reactive oxygen species (ROS). Beyond their established role in degradation and recycling, lysosomes occup...

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Bibliographic Details
Published in:Trends in biochemical sciences (Amsterdam. Regular ed.) 2021-12, Vol.46 (12), p.960-975
Main Authors: Rizzollo, Francesca, More, Sanket, Vangheluwe, Peter, Agostinis, Patrizia
Format: Article
Language:English
Subjects:
cancer
Cell Death - physiology
Ferroptosis
Iron - metabolism
iron homeostasis
iron trafficking
Lysosomes - metabolism
neurodegenerative diseases
Reactive Oxygen Species - metabolism
viruses
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Summary:Intracellular iron fulfills crucial cellular processes, including DNA synthesis and mitochondrial metabolism, but also mediates ferroptosis, a regulated form of cell death driven by lipid-based reactive oxygen species (ROS). Beyond their established role in degradation and recycling, lysosomes occupy a central position in iron homeostasis and integrate metabolic and cell death signals emanating from different subcellular sites. We discuss the central role of the lysosome in preserving iron homeostasis and provide an integrated outlook of the regulatory circuits coupling the lysosomal system to the control of iron trafficking, interorganellar crosstalk, and ferroptosis induction. We also discuss novel studies unraveling how deregulated lysosomal iron-handling functions contribute to cancer, neurodegeneration, and viral infection, and can be harnessed for therapeutic interventions. Iron homeostasis is achieved through finely tuned control of transport, storage, and compartmentalization.The endolysosomal system is central to all processes that control the trafficking, redistribution, and redox signaling properties of iron.Dynamic crosstalk between the lysosomes and mitochondria shapes the functional outcome of iron-dependent pathways.Iron metabolism in cancer cells sustains their plasticity and metabolic and epigenetic reprogramming.Lysosomal iron redox control can be therapeutically harnessed to induce ferroptosis in cancer cells.Iron dysregulation and lysosomal/mitochondrial dysfunction are increasingly recognized as major hallmarks of neurodegeneration.Iron homeostasis and endocytic pathways are hijacked by viruses to promote infection.
ISSN:0968-0004
1362-4326
DOI:10.1016/j.tibs.2021.07.003