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.

ATF3/SPI1/SLC31A1 Signaling Promotes Cuproptosis Induced by Advanced Glycosylation End Products in Diabetic Myocardial Injury

“…Metal dyshomeostasis at various levels of an organism is a common denominator and cause or consequence of many illnesses [ 5 ]. Defective copper regulation mediates cardiovascular damage through two general processes that occur simultaneously in the same individual: elevation of Cu(II)-mediated pro-oxidant stress and impairment of copper-catalyzed antioxidant defense mechanisms [ 4 , 10 ]. Low concentrations of copper ions through coronary perfusion could significantly reduce cardiac function [ 11 ].…”

“…The acquisition, distribution and elimination of metal micronutrients, such as iron (Fe) and copper (Cu), are essential for life [ 1 ]. Metabolic diseases such as diabetes, obesity and non-alcoholic fatty liver usually involve the interaction of multiple underlying molecular mechanisms [ 2 , 3 , 4 ]. Multiple lines of evidence have shown that metabolic diseases including obesity and diabetes are usually accompanied by the dysfunctional regulation of various metal ions [ 5 , 6 ].…”

Identification of copper death-associated molecular clusters and immunological profiles in rheumatoid arthritis

“…Thus, there is a relationship between RA and mitochondria. Copper death is a new mode of cell death that is distinct from iron death and necroptosis, and its related genes include SLC31A1, PDHB, PDHA1, LIPT1, FDX1, DLD, DLST, DBT, LIAS, DLAT, GCSH, ATP7A and ATP7B ( 15 , 16 ). The main mechanisms of copper death are the excessive accumulation of lipoylated mitochondrial enzymes and depletion of Fe-S cluster proteins ( 17 , 18 ).…”

Cardiometabolic Care: Assessing Patients with Diabetes Mellitus with No Overt Cardiovascular Disease in the Light of Heart Failure Development Risk

“…The effects of this pathological entity on cardiovascular health (CV) create further public health challenges and remain responsible for the increased prevalence of cardiovascular disease (CVD) [ 1 ]. Beyond coronary artery disease (CAD) progression, DM can precipitate or worsen heart failure (HF) due to multifactorial mechanisms (i.e., the accumulation of advanced glycation end products (AGEs), oxidative stress, inflammatory status impairment, decay of intracellular calcium, changes in microRNAs expression) [ 2 , 3 , 4 ]. Patients with diabetes develop HF at more than two-times the rate of patients without diabetes [ 1 ].…”