Transition metals and metal complexes in autophagy and diseases

Abstract

Transition metals refer to the elements in the d and ds blocks of the periodic table. Since the success of cisplatin and auranofin, transition metal‐based compounds have become a prospective source for drug development, particularly in cancer treatment. In recent years, extensive studies have shown that numerous transition metal‐based compounds could modulate autophagy, promising a new therapeutic strategy for metal‐related diseases and the design of metal‐based agents. Copper, zinc, and manganese, which are common components in physiological pathways, play important roles in the progression of cancer, neurodegenerative diseases, and cardiovascular diseases. Furthermore, enrichment of copper, zinc, or manganese can regulate autophagy. Thus, we summarized the current advances in elucidating the mechanisms of some metals/metal‐based compounds and their functions in autophagy regulation, which is conducive to explore the intricate roles of autophagy and exploit novel therapeutic drugs for human diseases.

The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy

“…To protect the cell from Cd toxicity, we assume that Cd-bound proteins can be recruited into aggregates and autophagosomes. This is in line with the emerging role of autophagy as a defense response to metals [32][33][34][35]. Cd could then bind a zinc-specific adaptor in a mechanism akin to selective autophagy.…”

“…At heart, the formation of protein aggregates, generally associated with neurodegenerative diseases, turns out to play a significant role in carcinogenesis by the sequestration and inactivation of two tumor suppressors, CYLD and selective autophagy, as previously reported for Tp53 family members [86,87]. Although we were unable to identify the initiating event, several lines of evidence suggest that selective autophagy may be a Zn-regulated process [32][33][34][35], in part because its selective cargo receptor SQSTM1 could bind Zn in a domain that links K63 Ub and LC3, and thus autophagosome formation [13,37]. Therefore, we propose that Cd ionic storm may displace Zn from the SQSTM1-dependent selective autophagy.…”

“…An alternative explanation for the accumulation of K63-linked ubiquitinated proteins besides the implication of proteasomes may concern defects in autophagy, a Zn-sensitive process that degrades K63-linked ubiquitinated cargos [5,9,[32][33][34][35]. Inline, Cd induced higher molecular weight (Hmw) forms of Beclin 1/BECN1, an essential component of PtdIns3K complexes that mediates the formation of autophagosomes.…”

“…Our study uncovers novel and critical consequences of Cd exposure at low subtoxic doses: Cd is the first example of a carcinogen that induces K63-linked ubiquitination. We propose that K63 ubiquitination resulted in part from the ability of Cd to mimic Zn and alert selective autophagy, a Zn sensing pathway that degrades K63-Ub proteins [5,9,[32][33][34][35]. One of the major events following Cd exposure is the accumulation of SQSTM1, a selective K63-Ub autophagy receptor, and an NF-κB signaling scaffold, which contains a Zn binding (ZZ) domain [13,[36][37][38].…”

Recent Advances in Transition-Metal Based Nanomaterials for Noninvasive Oncology Thermal Ablation and Imaging Diagnosis

“…Despite the successful application of cisplatin and aurein in clinics, transition-metal based nanomaterials have become a promising vehicle to deliver these drugs and have attracted much attention in the diagnosis and treatment of cancer ( Luo et al, 2021 ). According to the definition by the International Union of Pure and Applied Chemistry, transition metals have atoms with incomplete d subshell, common cation, or free atom ( Figure 2 ).…”