Mechanisms of cuproptosis
Recently we coined the term ‘cuproptosis’ to describe a specific, new form of regulated cell death that is induced by copper ionophores that bring copper into the mitochondria. First we established that cuproptosis is a distinct form of regulated cell death (different from apoptosis, ferroptosis and others). Second, whole genome CRISPR/Cas9 deletion screens revealed that the key regulators of cuproptosis are FDX1 and enzymes involved in cellular protein lipoylation. We have shown that in an FDX1 dependent manner mitochodiral copper can promote cell death by directly binding lipoylated proteins promoting their aggregation and also induce the global destabilization of Fe-S cluster proteins ultimately leading to cell death. Our current research focuse is on establishing the mechanistic principles that govern FDX1 regulation of cuproptosis, and revealing the downstream effectors processes that are essential for cell death (what the cells actually die from?).
Research Overview of the Tsvetkov Lab
Mechanisms regulating Cuproplasia
Unlike metabolites, metals cannot be created or destroyed. As such, metal homeostasis coordinated by metal uptake, trafficking and efflux pathways are essential to ensure the precise localization of metals, in the right amount at the right time in the cell. This is particularly important in the case of highly reactive transition metals such as copper. Copper regulated fitness impairments (cuproplasia) can occur through different genetic and environmental mechanisms. Our goal is to reveal and characterize these cuproplasia driving mechanisms. Combining functional genomics approaches along with metabolic and biochemical focused mechanistic validation experiments, we aim to resolve basic cell biology questions such as: (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) What signaling, metabolic, or viability regulating networks are directly regulated by metal availability promoting cellular fitness ?
