Cuproptosis: Unraveling the Mechanisms of Copper-Induced Cell Death and Its Implication in Cancer Therapy

Abstract

Copper, an essential element for various biological processes, demands precise regulation to avert detrimental health effects and potential cell toxicity. This paper explores the mechanisms of copper-induced cell death, known as cuproptosis, and its potential health and disease implications, including cancer therapy. Copper ionophores, such as elesclomol and disulfiram, increase intracellular copper levels. This elevation triggers oxidative stress and subsequent cell death, offering potential implications in cancer therapy. Additionally, copper ionophores disrupt mitochondrial respiration and protein lipoylation, further contributing to copper toxicity and cell death. Potential targets and biomarkers are identified, as copper can be targeted to those proteins to trigger cuproptosis. The role of copper in different cancers is discussed to understand targeted cancer therapies using copper nanomaterials, copper ionophores, and copper chelators. Furthermore, the role of copper is explored through diseases such as Wilson and Menkes disease to understand the physiological mechanisms of copper. Exploring cuproptosis presents an opportunity to improve treatments for copper-related disorders and various cancers, with the potential to bring significant advancements to modern medicine.

Cuproptosis: unveiling a new frontier in cancer biology and therapeutics

“…Investigations to pinpoint the precise mitochondrial respiration components affected by copper utilized inhibitors like Oligomycin, FCCP (Trifluoromethoxy carbonylcyanide phenylhydrazone), and antimycin A/rotenone, revealing a significant impact on the spare capacity of respiration, thus indicating the direct interaction of copper with the TCA cycle rather than with the electron transport chain (ETC) or adenosine triphosphate (ATP) synthesis components [ 1 ]. Genomic, metabolic, and individual gene knockouts have identified crucial genes for cuproptosis, classifying them into categories: FDX1, genes associated with the lipoic acid (LA) pathway (LIAS and LIPT1), and those part of the pyruvate dehydrogenase complex (PDC) crucial for mitochondrial respiration (DLAT; DLD: dihydrolipoamide dehydrogenase; PDHA1: pyruvate dehydrogenase E1 alpha 1 subunit; PDHB: pyruvate dehydrogenase E1 beta subunit), all linked to the LA pathway [ 122 ]. FDX1, potentially upstream in the LA pathway, aids in attaching the lipoyl group to DLAT, vital for the mitochondria the functionality of PDC [ 122 ].…”

“…Genomic, metabolic, and individual gene knockouts have identified crucial genes for cuproptosis, classifying them into categories: FDX1, genes associated with the lipoic acid (LA) pathway (LIAS and LIPT1), and those part of the pyruvate dehydrogenase complex (PDC) crucial for mitochondrial respiration (DLAT; DLD: dihydrolipoamide dehydrogenase; PDHA1: pyruvate dehydrogenase E1 alpha 1 subunit; PDHB: pyruvate dehydrogenase E1 beta subunit), all linked to the LA pathway [ 122 ]. FDX1, potentially upstream in the LA pathway, aids in attaching the lipoyl group to DLAT, vital for the mitochondria the functionality of PDC [ 122 ].…”