Tributyltin induces mitochondrial fission through Mfn1 degradation in human induced pluripotent stem cells

Area of Science:

• Toxicology
• Cell Biology
• Stem Cell Research

Background:

• Organotin compounds like tributyltin (TBT) are known endocrine disruptors and cytotoxic agents.
• TBT toxicity has not been previously characterized in normal stem cells.
• Human induced pluripotent stem cells (iPSCs) offer a model for studying cellular responses to environmental toxins.

Purpose of the Study:

• To investigate the effects of TBT on the viability and mitochondrial function of human iPSCs.
• To elucidate the mechanisms underlying TBT-induced cytotoxicity in stem cells.
• To explore the potential of using mitochondrial function as a biomarker for metal-induced toxicity.

Main Methods:

• Human iPSCs were exposed to nanomolar concentrations of TBT.
• Cell viability and intracellular ATP levels were measured.
• Mitochondrial morphology was assessed using MitoTracker staining.
• Expression of mitochondrial fusion protein mitofusin 1 (Mfn1) was analyzed.
• The role of E3 ubiquitin ligase MARCH5 was investigated using knockdown experiments.

Main Results:

• Nanomolar TBT exposure significantly decreased intracellular ATP levels and inhibited cell viability in iPSCs.
• TBT induced mitochondrial fragmentation, indicating altered mitochondrial dynamics.
• TBT exposure reduced Mfn1 expression.
• Knockdown of MARCH5 abolished the TBT-induced reduction in Mfn1 expression.
• These findings suggest TBT induces mitochondrial dysfunction via MARCH5-mediated Mfn1 degradation.

Conclusions:

• TBT exhibits cytotoxicity in human iPSCs at nanomolar concentrations.
• TBT disrupts mitochondrial function in stem cells, leading to fragmentation and impaired energy production.
• The MARCH5-mediated degradation of Mfn1 is implicated in TBT-induced mitochondrial dysfunction.
• Mitochondrial function in normal stem cells serves as a sensitive indicator for assessing metal-induced cytotoxicity.