A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system

Area of Science:

• Cell Biology
• Genetics
• Biochemistry

Background:

• Copper (Cu) is essential for aerobic organisms but cytotoxic if dysregulated.
• Genetic mutations affecting copper homeostasis cause severe clinical issues.
• Understanding cellular copper regulation is crucial for human health.

Purpose of the Study:

• To identify genes involved in copper homeostasis and its effect on cellular respiration.
• To explore the relationship between copper, iron uptake, and cellular pH.
• To investigate potential therapeutic interventions for copper-related disorders.

Main Methods:

• A large-scale (5050 strains) homozygous diploid deletion screen in yeast.
• Quantitative measurement of respiratory growth in response to copper addition.
• Analysis of gene functions and conservation in humans.

Main Results:

• Copper addition enhanced respiratory growth in yeast.
• 73 genes, including those involved in iron uptake, reduced this effect.
• 93 genes enhanced copper's positive effect on growth.
• Copper supplementation rescued respiratory defects in specific mutant strains.
• Identified genes linked to copper homeostasis, vacuolar pH, and previously unknown functions.
• Many identified genes are conserved in humans and associated with Mendelian disorders (e.g., Menkes, Wilson's disease).

Conclusions:

• A yeast functional screen identified novel genes critical for copper-dependent fitness.
• Perturbations in copper homeostasis impact cellular respiration and can be corrected pharmacologically.
• Findings reveal a complex cellular system for copper regulation with significant implications for human health and disease.