Copper Homeostasis in Diabetic Cardiomyopathy

Copper is a vital trace metal that serves as a cofactor for enzymes supporting mitochondrial oxidative phosphorylation, antioxidant defence and connective tissue integrity in the myocardium. In diabetes, persistent hyperglycaemia and metabolic dysregulation disrupt cellular copper balance, leading to either deficiency or overload. Copper deficiency impairs activity of copper-dependent enzymes such as superoxide dismutase and cytochrome c oxidase, resulting in oxidative stress, maladaptive remodelling and diminished contractile function. Conversely, copper overload triggers cuproptosis, a form of regulated cell death marked by aggregation of lipoylated mitochondrial proteins, loss of iron–sulphur cluster proteins and respiratory chain collapse. Aberrant expression and trafficking of copper transporters and chaperones—including CTR1, ATP7A and related intracellular carriers—further exacerbate this imbalance. Restoring copper homeostasis through selective chelation or judicious supplementation has emerged as a promising strategy to preserve myocardial structure and function. Given the global burden of diabetes and its cardiovascular complications, elucidating copper-mediated pathways offers potential therapeutic targets to mitigate heart failure risk in diabetic populations.

Research from Nature Portfolio

Recent studies have shown that systemic stressors such as sleep fragmentation exacerbate myocardial injury through copper-dependent mechanisms. In a murine model, chronic sleep fragmentation induced sympathetic overactivity and suppressed VPS35 expression, impairing ATP7A-mediated copper efflux. Resultant intracardiac copper accumulation promoted mitochondrial cuproptosis and apoptosis and worsened ischaemia–reperfusion injury. Both sympathetic denervation and administration of a copper chelator restored copper export, attenuated cuproptosis markers and improved cardiac recovery after injury, highlighting a neuro-hormonal link to copper overload in diabetic cardiomyopathy.

Copper Homeostasis in Diabetic Cardiomyopathy publication trend

The graph below shows the total number of articles in copper homeostasis in diabetic cardiomyopathy across all publications each year (not limited to Nature Index journals).

Technical terms

Diabetic cardiomyopathy: A disorder of the heart muscle in patients with diabetes, independent of coronary artery disease or hypertension.

Copper homeostasis: The regulation of copper uptake, distribution, storage and excretion to maintain optimal cellular function.

Cuproptosis: A form of regulated cell death triggered by excess intracellular copper that leads to mitochondrial dysfunction and protein aggregation.

Advanced glycation end products (AGEs): Harmful compounds formed by non-enzymatic reactions between sugars and proteins or lipids, accumulating in diabetes and contributing to tissue injury.

Copper chelator: A compound that binds copper ions, reducing their availability and mitigating copper-induced toxicity.

SLC31A1: A high-affinity copper importer on the cell membrane that regulates copper uptake into cells.

References

1. Sleep fragmentation exacerbates myocardial ischemia‒reperfusion injury by promoting copper overload in cardiomyocytes. Nature Communications (2024).
2. ATF3/SPI1/SLC31A1 Signaling Promotes Cuproptosis Induced by Advanced Glycosylation End Products in Diabetic Myocardial Injury. International Journal of Molecular Sciences (2023).
3. The Molecular Mechanisms of Defective Copper Metabolism in Diabetic Cardiomyopathy. Oxidative Medicine and Cellular Longevity (2022).
4. Ferroptosis, necroptosis and cuproptosis: Novel forms of regulated cell death in diabetic cardiomyopathy. Frontiers in Cardiovascular Medicine (2023).