The Molecular Mechanisms of Defective Copper Metabolism in Diabetic Cardiomyopathy

Abstract

Copper is an essential trace metal element that significantly affects human physiology and pathology by regulating various important biological processes, including mitochondrial oxidative phosphorylation, connective tissue crosslinking, and antioxidant defense. Copper level has been proved to be closely related to the morbidity and mortality of cardiovascular diseases such as atherosclerosis, heart failure, and diabetic cardiomyopathy (DCM). Copper deficiency can induce cardiac hypertrophy and aggravate cardiomyopathy, while copper excess can mediate various types of cell death, such as autophagy, apoptosis, cuproptosis, pyroptosis, and cardiac hypertrophy and fibrosis. Both copper excess and copper deficiency lead to redox imbalance, activate inflammatory response, and aggravate diabetic cardiomyopathy. This defective copper metabolism suggests a specific metabolic pattern of copper in diabetes and a specific role in the pathogenesis and progression of DCM. This review is aimed at providing a timely summary of the effects of defective copper homeostasis on DCM and discussing potential underlying molecular mechanisms.

Figure 1

Metabolic pathway of copper in human body. Transport route of copper in human body: oral intake, in the gastrointestinal tract absorption into the blood, the blood vessels in the copper blue protein combined with albumin and plasma protein transport via portal vein circulation to the liver [26, 30]. After the liver processing, the redistribution to the tissues and organs, such as the skeletal muscle, brain, and heart, widely participates in various life activities [13, 29]. Finally, through metabolism, bile enters the intestine and is excreted in the stool or through the kidney and is excreted in the urine [31, 32]. ATP7A: adenosine triphosphatase 1; CTR1: copper transporter 1; MT: metallothionein (storage of cytosol exceeding copper); SOD1: Cu/Zn superoxide dismutase; GSH: glutathione; CP: ceruloplasmin.

Figure 2

Copper ion-mediated cell death in DCM. Copper can mediate various types of cell death in vivo, mainly including apoptosis, autophagy, pyroptosis, and cuproptosis recently discovered via copper-mediated. The different apoptosis pathways are triggered by copper at different time points of the exposure period, as the increase in transcripts was sequential [121]. Apoptosis mainly occurs in mitochondria, nucleus, and endoplasmic reticulum. Autophagy is mainly due to the activation of mTOR-ULK1/2 signaling pathway by copper ion, which is a self-protection mechanism of the body, but excessive autophagy can cause pathological damage to the body [122]. Pyroptosis is caused by copper ion through Fenton/Haber Weiss reactions that occur and involve destructive cell death mediated by ROS [123, 124]. Cuproptosis mainly occurs in cells with high energy demand and abundant mitochondria. Excessive copper ions participate in TCA process under the action of FDX1, which can induce DLAT aggregation and lead to abnormal mitochondrial protein folding, followed by the loss of Fe-S protein, resulting in cell death due to energy metabolism defects [125]. Besides, copper ions can lead to redox imbalance, and the antioxidant defense of GSH and SOD is insufficient to resist the damaging effect of ROS [13].