Shaoping Zhang, Hong Liu, Greeshma V Amarsingh, Carlos C H Cheung, Umayal Narayanan, Lin Zhang and Garth J S Cooper
University of Auckland, New Zealand
Posters & Accepted Abstracts: J Diabetes Metab
Sustained hyperglycemia in diabetic patients develops cardiomyopathy and heart failure for which cardiac mitochondrial dysfunction is the key feature. This study aimed to investigate how defective copper regulation may affect cardiac mitochondrial function and to evaluate the effects of Cu(II)-chelation by triethylenetetramine (TETA), on reversibility of mitochondrial activity in diabetic cardiomyopathy (DCM). Cardiac-dysfunction was assessed in STZ-diabetic and TETA-treated STZ-diabetic rat using ex-vivo perfusion of isolated heart. DCM with copper deficiency was associated with reduction in myocardial expression of mitochondrial copper chaperones COX17, COX11, SCO1 and CCS which could result in defective copper delivery/utilization and assembly of mitochondrial resided cytochrome c oxidase (CCO) and Cu/Zn superoxide dismutase (SOD1), and subsequently decreased activities of these enzymes. The improvement in cardiac function by TETA treatment was accompanied by amelioration of expression of these copper chaperones: Leading to increased copper supply to mitochondria, and activation of CCO and SOD1 activities. TETA treatment also ameliorates decreased expression of the key mitochondrial metabolic regulator peroxisome proliferator-activated receptor gamma co-activator-1 (PGC-1) in diabetic heart, whereas by contrast, it has no effects on increased mitochondrial biogenesis which is consistent with the compensatory responses for decreased mitochondrial activity in diabetes. In this study, we have identified a dysregulation of mitochondrial copper transport pathway which impairs cardiac mitochondrial respiration and antioxidant activity in diabetic heart. We also demonstrated a novel beneficial effect of TETA on DCM that involved chelator-mediated restoration of mitochondrial copper homeostasis and anti-oxidant defenses, as well as improvement of mitochondrial metabolism, which may represent a promising therapy for DCM.
Email: s.zhang@auckland.ac.nz
