Mechanisms Regulating Cuproplasia

Unlike metabolites, metals cannot be created or destroyed. Therefore, maintaining metal homeostasis through precise regulation of uptake, trafficking, and efflux pathways is critical for cellular function. This is especially true for highly reactive transition metals like copper, where even slight imbalances can have significant consequences. Copper-regulated fitness impairments (cuproplasia) can occur through different genetic and environmental  mechanisms. In our lab, we previously identified and characterized a new form of regulated cell death, termed “cuproptosis,” caused by mitochondrial copper accumulation. Building on this discovery, our current research aims to uncover additional mechanisms driving cuproplasia through chemical genomic approaches.
Key questions guiding our work include:: (i) What are the genes and mechanisms involved in copper trafficking (transporters and chaperones), intracellular distribution (specific organelle compartmentalization), and toxicity (cell death mechanisms)? (ii) What are the common and shared stress response pathways associated with cuproplasia? (iii) How do signaling, metabolic, or viability-regulating networks respond to metal availability to promote cellular fitness?
By addressing these questions, we aim to provide a comprehensive understanding of copper’s role in cellular physiology and its potential as a therapeutic target in diseases driven by metal imbalances.