Page 68 - MI-2-1

Microbes & Immunity Copper and cuproptosis in immunity

Copper is an essential nutrient that plays a role in against heavy metal toxicity. It has been suggested that
15
various biological processes involving bacteria, such as glutathione may bind to copper, disrupting the activity of
redox reactions, protein synthesis, and cell signaling. Fe-S cluster enzymes. In the absence of oxygen atoms,
5
16
In addition, copper can promote bacterial growth and copper replaces iron in Fe-S clusters, forming sulfur
development. However, for bacteria, copper is a double- bridges with copper instead. Fe-S clusters are organic metal
6
edged sword; while trace amounts of copper can stimulate components of iron and sulfur responsible for biological
bacterial growth, an excess of copper can lead to bacterial electron transfer, serving as storage reservoirs for iron
death. Compared to other forms of programmed cell and sulfur, and playing roles in genome stability and
7
death, copper-induced cell death, known as cuproptosis, nucleic acid metabolism. Their inactivation leads to the
17
represents a novel mechanism of cell death. Studies have downregulation of several key metabolic enzymes, driving
8
shown that copper ions can induce cell death through cells into a toxic stress state and ultimately resulting in
mitochondrial sulfurtransferase A. When copper ions bind their demise.
to the sulfurtransferase A protein in the mitochondria,
they inhibit the protein’s activity, leading to protein toxicity Copper is primarily absorbed in the small intestine,
stress response and ultimately resulting in cell death. where it is taken up by intestinal cells and transported
9
18
Moreover, copper can induce cell death through oxidative into the bloodstream. This process relies on specific
19
10
stress mediated by lipid acylation proteins. Bacteria transporters, such as copper transporter 1 (CTR1). Once
experience copper-related cell death when exposed to in the bloodstream, copper is predominantly carried by
copper. Copper death, as a type of programmed cell death, proteins such as albumin and ceruloplasmin (plasma
ceruloplasmin) to various tissues throughout the body.
20
may allow bacteria to program a response when faced
with pressure from copper ions. Using this mechanism, it Within cells, copper is directed to different organelles,
is possible to leverage cuproptosis to initiate bacterial cell including the mitochondria and the endoplasmic
21
death under specific therapeutic conditions, to clear the reticulum. The liver plays a crucial role in copper
22
infection. At the same time, appropriate concentrations of storage; liver cells can store copper and release it into the
copper enhance the response of the host immune system bloodstream as needed. This regulation involves several
23
and strengthen the function of macrophages and other proteins, such as metallothionein. Excess copper is
immune cells, thereby contributing to infection control. excreted from the body through bile, and the mechanisms
This review primarily summarizes the mechanisms governing copper excretion are influenced by the
24
underlying bacterial cuproptosis, aiming to provide novel physiological state and copper levels in the body.
application insights. 3. Effects of copper metabolism disorders
2. Cuproptosis and copper metabolism on human
Copper-mediated bacterial cell death, also known as Following the normal physiological processes of copper
cuproptosis, refers to the process of bacterial demise absorption, transportation, and distribution within
triggered by the toxic effects of copper ions. This unique the body as described above, any disruption in these
mechanism of bacterial cell death heavily relies on the finely tuned mechanisms can lead to the onset of copper
toxicity of copper ions to eradicate bacteria. Several studies metabolism disorders. Copper is an essential trace element
11
have elucidated the potential mechanisms underlying involved in a variety of physiological functions, including
copper toxicity observed across various microbial genera. enzyme activity, antioxidant defense, iron metabolism,
25
Among these, the most recognized mechanism involves and nerve conduction. However, an excess or deficiency
copper ions mediating the Fenton reaction, leading to the of copper in the body can cause serious health problems
generation of oxygen atoms and hydroxyl radicals (reactive (Table 1). Wilson’s disease and Mendelian diseases
oxygen species [ROS]) that inflict oxidative damage on characterized by copper deficiency can be grouped under
12
macromolecules such as proteins, lipids, and DNA. While the umbrella of copper metabolism disorders. The proper
low concentrations of copper ions are essential for bacteria regulation of copper levels is thus of utmost importance for
and participate in various biological processes such as cell maintaining overall health and homeostasis.
growth and differentiation, high concentrations can induce Wilson’s disease is a genetic disorder primarily caused by
cuproptosis in bacteria. 13 mutations in the ATP7B gene, leading to a deficiency in a

An increase in copper (II) ion concentration results in copper-transporting protein crucial for copper excretion in
a sharp rise in ROS levels, leading to decreased survival the liver. This deficiency results in copper accumulation and
of mycobacteria. Furthermore, copper has been shown damage in various tissues, including the liver, brain, kidneys,
14
to deplete glutathione, a crucial antioxidant that protects and eyes. Symptoms of Wilson’s disease can be diverse,
26
Volume 2 Issue 1 (2025) 60 doi: 10.36922/mi.5657