Copper - a novel stimulator of autophagy

Abstract

Toxic copper accumulation causes Wilson disease, but trace amounts of copper are required for cellular and organismal survival. In a recent paper Tsang et al. (Nat Cell Biol, doi: 10.1038/s41556-020-0481-4) demonstrate that copper binds with high affinity to a designated interaction site in the pro-autophagic kinases ULK1 and ULK2. Chelation of copper or genetic deletion of this copper-binding site inhibits autophagy and hence reduces the fitness of KRAS-induced cancers. These findings suggest that copper chelation might constitute a novel therapeutic intervention on autophagy-dependent malignancies.

Keywords: MEK1; ULK1; ULK2; Wilson disease; autophagy; cancer; copper.

Figure 1. FIGURE 1: Copper-driven autophagy and its impact on Wilson disease and cancer.

Cellular copper entry occurs via the transporter CTR1, and its efflux is driven by ATP7A (impaired in Menkes disease, or by ATP7B that is impaired in Wilson disease). High-affinity chelators, CTR1 depletion or ATP7A overexpression reduce the available intracellular copper-pool that otherwise may bind to autophagy activating kinases ULK1 and 2. Upon amino acid deprivation, mTOR kinase activity is reduced, thereby initiating the autophagic process in dependence of ULK1/2. In Wilson disease, excessive copper accumulates in mitochondria, causing bioenergetic deficits, thus providing a further pro-autophagic signal, and copper-burdened mitochondria are subjected to autophagic degradation. In certain types of cancer (e.g. KRAS^G12D lung adenocarcinomas), copper activates MAPK signaling via MEK1 besides ULK1/2 activation, thereby providing a dual signal that improves cancer cell survival and proliferation.