Integrative analysis of copper dysregulation and cuproptosis in postnatal hematopoiesis

Copper dysregulation has been linked to human health, disorders, and hematopoiesis. However, the underlying mechanisms remain elusive. Here, we demonstrate the pivotal role of dietary copper via the transporter Slc31a1(Ctr1) in copper homeostasis, but not cuproptosis, during postnatal hematopoiesis. Specifically, Slc31a1-mediated copper uptake sustains the differentiation and commitment of multipotent progenitors from short-term hematopoietic stem cells (HSCs). Using transcriptomic analyses, we reveal a disrupted differentiation program in hematopoietic stem and progenitor cells (HSPCs) in diet-induced copper-deficient mice or hematopoietic-specific Slc31a1 knockout (vKO) mice. Further, we show that Slc31a1 and copper are indispensable for sustaining mitochondrial activity via regulating Mtco1 and Mtco2 (subunits of Complex IV) within HSPCs. Notably, we show that the chemical compound elesclomol, also well-known as a potent cuproptosis agonist, significantly alleviates severe anemia and partially recovers HSPC mitochondrial function in vKO mice via its activity as a copper ionophore, but with no effect on cuproptosis. We thus renamed elesclomol as CupriActivitor1(CuA1), which is a more specific and descriptive term. These findings demonstrate the critical role and mechanism of copper, Slc31a1, and CuA1 in maintaining HSC homeostasis via modulation of mitochondrial energy metabolism. The study sheds light on the molecular basis of HSC fate decisions by copper or CuA1 and opens new avenues for the development of novel therapeutic strategies for copper-related disorders and blood diseases. Given the critical and multifaceted nature of copper, we propose establishing a novel interdisciplinary field termed "Cuprology". This discipline will advance our understanding of copper's roles in physiological and pathological processes.