Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/28/2008
Publication Date: 7/3/2008
Citation: Johnson, W.T., Johnson, L.K. 2008. Copper Deficiency Inhibits CA2+-Induced Swelling in rat Cardiac Mitochondria. Journal of Nutritional Biochemistry.doi.10.1016/j.jnutbio.2008.02.009
Interpretive Summary: Experiments with laboratory animals have implicated low dietary copper intake as a potential risk factor for heart disease. Mechanisms underlying the detrimental effects of low copper intake on the heart include overproduction of reactive oxygen and nitrogen compounds that can cause cellular damage, altered formation of blood vessels, and defective mitochondrial function. Mitochondria, in addition to producing energy for the cell, can release chemicals that activate pathways leading to cell death. Release of the chemicals involved in cell death depends on the formation of a channel called the permeability transition pore in the mitochondrial membranes that allows the chemicals to exit the mitochondria. An increase in ionic calcium in the cell is one of the stimuli that can promote cell death by causing formation of the permeability transition pore. Results from the present study show that copper deficiency impairs permeability transition pore formation in rat heart mitochondria following stimulation with ionic calcium. Impaired permeability transition pore formation may be a response that helps protect the heart cells from cell death during copper deficiency, but it may also mean that the calcium transport mechanism responsible for initiating pore formation was damaged by copper deficiency. Thus, instead of a protective response, the impairment of pore formation may indicate that heart mitochondria are less able to regulate fluctuations in cellular calcium concentrations. Such an impairment in the cell’s ability to regulate calcium can be detrimental to the heart.
Technical Abstract: Copper deficiency disrupts the architecture of mitochondria, impairs respiration and inhibits the activity of cytochrome c oxidase, the terminal, Cu-dependent respiratory complex (complex IV) of the electron transport chain. This suggests that perturbations in the respiratory chain may contribute to the changes in mitochondrial structure caused by Cu deficiency. This study investigates the effect of Cu deficiency on Ca2+-induced mitochondrial swelling as it relates to changes in respiratory complex activities in cardiac mitochondria of rats. Male weanling rats were fed diets containing either no added Cu (Cu0), 1.5 mg Cu/kg (Cu1.5), 3mg Cu/kg (Cu3), or 6 mg Cu/kg (Cu6). The rate of Ca2+-induced mitochondrial swelling in the presence of succinate and oligomycin was reduced and the time to reach maximal swelling was increased only in the rats consuming Cu0 diet. Cytochrome c oxidase activity was reduced 60% and 30% in rats fed Cu0 and Cu1.5, respectively, while NADH:cytochrome c reductase ( complex I+complexIII) activity was reduced 30% in rats consuming both Cu0 and Cu1.5. Mitochondrial swelling is representative of mitochondrial permeability transition pore (MPTP) formation and the results suggest that Ca2+-induced MPTP formation occurs in cardiac mitochondria of Cu-deficient rats only when cytochrome c oxidase activity falls below 30% of normal. Decreased respiratory complex activities caused by severe Cu deficiency may inhibit MPTP formation by increasing matrix ADP concentration or promoting oxidative modifications that reduce the sensitivity of the calcium trigger for MPTP formation.