Date of Award

3-8-1994

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Physiology and Pharmacology

Abstract

Morphological observations indicate that dietary copper deficiency causes structural damage to cardiac mitochondria. Even though marked structural changes have been observed in copper deficiency, a correlation between abnormality of mitochondrial structure and function has not been apparent in previous studies. The objective of the present project was to examine various aspects of cellular and mitochondrial function in copper deficient rat hearts; especially, (1) changes in mitochondrial function defined as respiration and ATP production, (2) the susceptibility of the mitochondria from copper deficient rat hearts to uncouplers and inhibitors of oxidative phosphorylation and electron transport, and (3) alterations in the activity, function, and or expression of enzymes or proteins that are related to cardiac or mitochondrial function. Rats were fed diets deficient (CuD, ${<}1\ \mu$g/g) or adequate (CuA, 5 $\mu$g/g) in copper for 4 weeks. Mitochondria were isolated from hearts of CuA and CuD rats. State 4 and state 3 respiration rates were decreased with all substrates tested, but the ADP/oxygen consumed ratio and acceptor control index were not significantly affected by copper deficiency. A variety of inhibitors and uncouplers of oxidative phosphorylation were tested. An incomplete blockade of respiration with oligomycin in copper deficiency indicated that the ATP synthase was a possible site of alteration. In addition, decreased expression of specific stress-induced proteins, including mitochondrial heat shock protein 60, suggested that at least one endogenous protective mechanism was impaired by copper deficiency. These results indicate that the structural morphology observed in copper deficiency is accompanied by definite cellular and molecular alterations in cardiovascular function.

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