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Iron-induced cytotoxicity mediated by endolysosomal TRPML1 channels is reverted by TFEB.
- Source :
-
Cell death & disease [Cell Death Dis] 2022 Dec 16; Vol. 13 (12), pp. 1047. Date of Electronic Publication: 2022 Dec 16. - Publication Year :
- 2022
-
Abstract
- Increased brain iron content has been consistently reported in sporadic Parkinson's disease (PD) patients, and an increase in cytosolic free iron is known to cause oxidative stress and cell death. However, whether iron also accumulates in susceptible brain areas in humans or in mouse models of familial PD remains unknown. In addition, whilst the lysosome functions as a critical intracellular iron storage organelle, little is known about the mechanisms underlying lysosomal iron release and how this process is influenced by lysosome biogenesis and/or lysosomal exocytosis. Here, we report an increase in brain iron content also in PD patients due to the common G2019S-LRRK2 mutation as compared to healthy age-matched controls, whilst differences in iron content are not observed in G2019S-LRRK2 knockin as compared to control mice. Chemically triggering iron overload in cultured cells causes cytotoxicity via the endolysosomal release of iron which is mediated by TRPML1. TFEB expression reverts the iron overload-associated cytotoxicity by causing lysosomal exocytosis, which is dependent on a TRPML1-mediated increase in cytosolic calcium levels. Therefore, approaches aimed at increasing TFEB levels, or pharmacological TRPML1 activation in conjunction with iron chelation may prove beneficial against cell death associated with iron overload conditions such as those associated with PD.<br /> (© 2022. The Author(s).)
- Subjects :
- Humans
Mice
Animals
Iron metabolism
Calcium metabolism
Lysosomes metabolism
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism
Transient Receptor Potential Channels genetics
Transient Receptor Potential Channels metabolism
Iron Overload metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 13
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 36522443
- Full Text :
- https://doi.org/10.1038/s41419-022-05504-2