Link Between Nickel Toxicity and Sterol Biosynthesis

Researchers at the University of Georgia recently made an interesting discovery about how nickel, a toxic metal, affects cells. Their findings, published in the journal PLoS Genetics, reveal that exposure to nickel can lead to a sterol deficiency in both mammalian (animals) and fungal cells.

Key-Findings

The research team discovered an unexpected connection between nickel exposure and sterol biosynthesis (the process of creating sterols) in fungal and mammalian cells. Here's a summary of their findings:

• Nickel Exposure Reduces Sterol Levels: When exposed to nickel, cells in both fungi and mammals had reduced amounts of sterols. Specifically, in fungi, the sterol ergosterol was significantly decreased.
• The Role of SRE1/SREBP: The researchers found that a specific protein called SRE1 (Sterol Response Element 1) in fungi is important for regulating sterol production. In mammals, a similar protein is called SREBP (Sterol Regulatory Element Binding Protein). When cells are exposed to nickel, this protein is activated and triggers the genes responsible for sterol biosynthesis.
• The Gene ERG25 and Nickel Tolerance: One crucial finding of the study was that a gene called ERG25, which is involved in sterol biosynthesis, plays a role in nickel tolerance. When the ERG25 gene was over-expressed (increased activity), fungal cells were better able to tolerate high levels of nickel. This suggested that the ERG25 protein helps the cell deal with nickel exposure by maintaining sterol production.
• Sterol Deficiency and Nickel Sensitivity: The study also found that fungal cells with a mutation in the Sre1 gene (which controls sterol biosynthesis) became very sensitive to nickel. Without proper sterol production, these cells couldn’t handle the stress caused by nickel, highlighting the link between sterol biosynthesis and nickel tolerance.

How does it connect to cell biology and potential medical applications?

• Nickel and Its Role: Nickel is a heavy metal often found in industrial environments, and it's also a known allergen and carcinogen for humans. However, certain organisms, such as plants, bacteria, and fungi, actually need nickel for normal biological processes. For example, the fungus Cryptococcus neoformans uses nickel for the function of an important enzyme called urease.
• Sterols and Their Importance: Sterols are lipid molecules (fats) that are a critical component of cell membranes in plants, animals, and fungi. They provide structural rigidity to these membranes, making them more stable. In humans and animals, the most important sterol is cholesterol, while in fungi, it is ergosterol.
  • Cholesterol: In humans, cholesterol is essential for many bodily functions, but if present in excess, it can build up in blood vessels and cause heart disease.
  • Ergosterol: In fungi, ergosterol plays a similar role to cholesterol but is the target of many antifungal drugs, like fluconazole, which inhibit ergosterol production to kill the fungus.