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Denis Medeiros

Professor
Research Areas:

The trace element copper is an essential nutrient.  Most of its physiological impact is due to its role as a  co-factor for approximately 12 enzymes.  Some of these enzymes include cytochrome c oxidase, superoxide dismutase, and lysyl oxidase.  One significant aspect of copper is that when copper is absent in the diets of rodents and/or swine, cardiac hypertrophy ensures within 3 to 6 weeks depending on the time of dietary restriction.  Electrocardiography and echocardiography both report that these hearts are clinical compromised. The type of cardiac hypertrophy exhibited is somewhat unusual and most resembles mitochondrial diseases that affect the heart.  Transmission electron microscopy studies reveal that there is a greater volume density of mitochondria in hearts from copper-deficient rats, for instance, than those fed adequate levels of copper.   Lipid droplets and glycogen granules are increased in these diseased hearts. The mitochondria do not appear normal as there is significant vacuolization.  Our research has focused on what triggers mitochondrial biogenesis in the heats of copper deficient rats.  Our first focus was on the enzyme cytochrome c oxidase as this is a cupro-enzyme.  This is perhaps one of the most important enzymes in cells as it is involved in the electron transport production of ATP.  We reported that in copper deficiency the copper-containing mitochondrial encoded subunits appear to have normal levels of these transcripts, but the nuclear encoded peptides have markedly  decreased levels of mRNA transcripts.  Furthermore, looking into the gene program that regulates mitochondrial biogenesis, several key transcription factors are upregulated according to our findings: 1) mitochondrial transcription factor A (mtTFA); 2) Nuclear Respiratory Units 1 and 2 (NRF-1 and NRF-2), and the proposed master regulator of mitochondrial biogenesis, peroxisomeproliferator-activated receptor gamma co-activator 1-alpha (PGC-1α).  It is important to note that ATP levels of the hearts from copper-deficient rats are normal.  This would suggest that the mitochondrial biogenesis is initiated to meet the enrgy demands of the heart. While there is some tricuspid and bicuspid dysfunction in copper deficient rat hearts, likely due to impaired lysyl oxidase activity, this role is thought to be small compared to the mitochondria pathology.

The role of copper in human heart disease is uncertain.  According to animal studies, the copper deficiency must be severe to observe these pathologies, although there are genetic abnormalities of copper absorption leading to some of the heart issues. Over the years the requirement and recommendations for copper has varied, but more recently a Dietary Recommended Allowance of 0.9 µg/day has been established.  In previous years the recommendation ranged as high as 3 µg/day.  It is doubtful based on human studies that those with levels slightly below the recommended levels, typical in some Western diets, would have cardiac problems due to a lack of copper.

Selected Publications

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AC 342
235-1301