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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Healthy Body Weight Research » Research » Publications at this Location » Publication #181570


item Johnson, William

Submitted to: Experimental Biology and Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/21/2005
Publication Date: 2/1/2006
Citation: Johnson, W.T., Brown-Borg, H.M. 2006. Cardiac cytochrome-c oxidase deficiency occurs during late postnatal development in progeny of copper-deficient rats. Experimental Biology and Medicine. 231:172-180.

Interpretive Summary: Estimates of usual copper intakes from food indicate that up to 90% of pregnant women and up to 95% of lactating women do not meet either the estimated average requirement (EAR) or recommended dietary allowance (RDA) for copper. These results indicate that copper intakes below the EAR and RDA are not uncommon for pregnant and lactating women. Although it is not known what effect maternal copper deficiency has on human fetal development, studies with animals have shown that copper deficiency during pregnancy and lactation results in abnormal fetal and postnatal development of the central nervous system. However, little is known about the importance of copper for the development of the cardiovascular system. The heart in neonatal rats is not completely developed until about two weeks after birth. During this period, the activities of a class of mitochondrial enzymes needed to satisfy the energy requirements of the developing, growing heart increase. The activity of one of these enzymes, cytochrome c oxidase, depends on copper. This study shows that copper deficiency in rats during pregnancy and lactation reduces cytochrome c oxidase activity in the developing heart of neonates. Furthermore, the reduction of activity occurs not only as a result of copper deprivation to the enzyme, but also as a reduction in the mitochondrial content of cytochrome c oxidase. Thus, maternal copper deficiency caused an acquired cytochrome c oxidase deficiency in the neonatal heart mitochondria. The cytochrome c oxidase deficiency also was not completely restored by providing the neonates with an adequate supply of dietary copper after they were weaned. Cytochrome c oxidase deficiency is associated with some forms of heart disease and the findings from this study suggest that copper-deficiency in pregnant and lactating women may increase their children’s risk for developing heart disease at some time during their lifetimes.

Technical Abstract: Although cytochrome c oxidase (CCO) is a Cu-dependent enzyme, the effect of maternal Cu deficiency on the expression of CCO activity during postnatal development of the neonatal rat heart has not been investigated extensively. Here we show that CCO activity in heart mitochondria isolated from neonates of Cu-deficient dams did not exhibit significant reductions until postnatal days 15 and 21. In addition, immunoblot analysis indicated that subunit 1 of CCO (COX1) was reduced on postnatal days 10 and 21 and subunit 4 (COX4) was reduced on postnatal day 21 in heart mitochondria of the neonates from Cu-deficient dams. These findings indicate that the impairment of CCO activity in neonatal heart by maternal Cu deficiency occurs late in the postnatal heart development. Furthermore, the reductions in COX1 and COX4 suggest that the impaired CCO activity reflects a CCO deficiency in heart mitochondria in addition to lower enzymatic activity resulting from a limited supply of Cu to the active site of the enzyme. CCO activity, COX1, and COX4 in heart mitochondria were not fully restored by 6 wk of postweanling Cu supplementation in the progeny of Cu-deficient dams. Also, NADH cytochrome c reductase activity, which represents the combined activities of respiratory complexes I and III, and the 39 kDa subunit of respiratory complex I were reduced in the Cu-supplemented progeny of the Cu-deficient dams. This indicates that maternal Cu deficiency produced defects in CCO and respiratory complex I during late postnatal heart development that once established, are difficult to correct by supplementation with adequate dietary Cu.