Transition metals activate TFEB in overexpressing cells

Area of Science:

• Cell Biology
• Toxicology
• Neuroscience

Background:

• Transition metal toxicity contributes to human diseases, including neurodegenerative disorders.
• Lysosomes play a key role in managing cellular transition metals.
• Transcription factor EB (TFEB) regulates lysosomal function and cellular stress responses.

Purpose of the Study:

• To investigate the role of TFEB in cellular responses to transition metal exposure.
• To determine if TFEB activation influences transition metal toxicity.
• To explore the therapeutic potential and limitations of TFEB modulation.

Main Methods:

• Exposure of cells to transition metals (copper and iron).
• Assessment of TFEB activation and TFEB-dependent gene expression.
• Evaluation of cellular responses including oxidative stress and mitochondrial damage.
• Analysis of lysosomal exocytosis levels.

Main Results:

• Copper and iron activated TFEB and stimulated TFEB-dependent gene expression.
• TFEB was cytoprotective against moderate copper exposure by reducing oxidative stress.
• Overexpressed TFEB exacerbated toxicity, oxidative stress, and mitochondrial damage at high copper levels, especially in cells with low lysosomal exocytosis.

Conclusions:

• The TFEB-driven gene network is integral to the cellular response to transition metals.
• TFEB activation has a dual role in transition metal toxicity, dependent on exposure levels and cellular context.
• TFEB overexpression presents potential toxicity and limitations as a therapeutic strategy.