Copper deficiency: A potential model for determining the role of mitochondria in cardiac aging

Abstract

Heart mitochondria experience age-related declines in cytochrome c oxidase (CCO) activity and increases in the generation of reactive oxygen species (ROS) that may contribute to loss of cardiac function and the development of disease that occur with advancing age. In a manner similar to aging, copper deficiency also suppresses heart CCO activity and has cardiovascular consequences related to increased peroxidation. Food restriction is often used as a tool to study oxidative mechanisms of aging and the present study examines the potential of copper deficiency to model the role of mitochondria in cardiac aging by determining if the effect of food restriction on CCO activity and oxidative stress in heart mitochondria parallels its effect on cardiac mitochondria during aging. Overall, copper deficiency severely inhibited CCO activity and increased both Mn superoxide dismutase (MnSOD) and glutathione peroxidase (GPX) in isolated heart mitochondria. However, a 20% reduction in food intake by copper-deficient rats increased CCO activity by 65% and decreased MnSOD activity by 25% but had no effect in rats fed adequate copper. Copper deficiency also reduced the carbonyl content of 80-100 kDa mitochondrial proteins, but the reduction in carbonyl content was unaffected by food restriction. Food restriction did, however, completely prevent the enlargement of cardiac mitochondria in copper-deficient rats. Together, these findings indicate that copper deficiency induces mitochondrial antioxidant enzyme activity and hypertrophy in cardiac tissue in response to reduced CCO activity and that food restriction may counteract these changes by reducing oxidative stress. Because the action of food restriction on CCO activity and mitochondrially generated oxidative stress are similar in copper deficiency and aging, copper deficiency may serve as a short-term model for studying the potential roles of mitochondria in cardiac aging.

Copper deficiency may be a leading cause of ischaemic heart disease

“…Cytochrome c activity is positively correlated with copper concentrations in copper-deficient and copper-sufficient rats, indicating another mechanism through which copper concentrations affect mitochondrial function. 41 A decline in cytochrome c oxidase (CCO) activity is characteristic of the ageing heart, and copper deficiency causes the same phenomenon. Reduced CCO activity in turn leads to cardiac hypertrophy.…”

“…Copper deficiency in experimental animals can be used as a model for studying the place of mitochondrial function in the ageing heart. 41 Mitochondria of copper-deficient rats consume oxygen at a significantly lower rate than those of copper-sufficient rats; they have a lower membrane potential and an altered ATP synthase complex, indicating lower rates of energy production. 42 …”

Micronutrient deficiencies in heart failure: Mitochondrial dysfunction as a common pathophysiological mechanism?

“…Although copper is crucial for cytochrome oxidase function, the transporters and regulators of mitochondrial copper are unknown. In rats, a copper-deficient diet caused a 74% decrease in CCO and increased manganese superoxide dismutase (MnSOD) and GPX in isolated heart mitochondria [150,151]. This is an indirect indication that mitochondrial ROS production was increased [151].…”

“…In rats, a copper-deficient diet caused a 74% decrease in CCO and increased manganese superoxide dismutase (MnSOD) and GPX in isolated heart mitochondria [150,151]. This is an indirect indication that mitochondrial ROS production was increased [151]. Moreover, specifically cardiac mitochondrial ETC function was compromised in copper-deficient rats [55].…”

Dietary Copper Deficiency Leads to Changes in Gene Expression Indicating an Increased Demand for NADH in the Prefrontal Cortex of the Rat’s Brain

“…Cu is an essential component of the mitochondrial complex IV (cytochrome C oxidase) [ 10 , 11 ]. In Johnson and Newman’s study (2003), a Cu-deficient diet in rats resulted in a decrease in cytochrome C oxidase, an increase in manganese superoxide dismutase (MnSOD), and glutathione peroxidase (GPX) in isolated cardiac mitochondria [ 22 ]. Chen et al study (2002) demonstrated impaired cardiac mitochondrial respiration in rats with a Cu-deficient diet [ 23 ].…”