This revised application proposes to study the hypothesis that the impact of copper (Cu) deficiency on the heart acts as if it is due to a mitochondrial genetic disease which influences mitochondrial biogenesis, and that this effect is mediated by up-regulation of transcriptional factors which are responsible for the pathology and biochemistry. These changes include decreases in cytochrome c oxidase (CCO) activity and absolute amounts of the nuclear--encoded peptide subunits. In addition, the delta subunit of ATP synthase is markedly decreased and the e subunit of ATPase is significantly increased. These changes would induce the mitochondrial biogenesis and subsequent increase in cardiac mass that is observed in the hearts from copper-deficient rats. This proposal thus will examine three specific aims: 1. To determine if the expression and DNA binding activity of several transcriptional factors, know to regulate nuclear and mitochondrial encoded genes, are increased in hearts from copper deficient rats. 2. To determine if the gene regulatory program involved in mitochondrial biogenesis in copper deficiency is similar to the pressure-overload induced model of myocyte hypertrophy and 3. To determine if the functional properties of ATP synthase and inhibitory ATP synthase protein are decreased in hearts from copper-deficient rats.
| Chen, Xiulian; Medeiros, Denis M; Jennings, Dianne (2005) Mitochondrial membrane potential is reduced in copper-deficient C2C12 cells in the absence of apoptosis. Biol Trace Elem Res 106:51-64 |
| Chen, Xiulian; Jennings, Dianne B; Medeiros, Denis M (2002) Impaired cardiac mitochondrial membrane potential and respiration in copper-deficient rats. J Bioenerg Biomembr 34:397-406 |
| Mao, S; Leone, T C; Kelly, D P et al. (2000) Mitochondrial transcription factor A is increased but expression of ATP synthase beta subunit and medium-chain acyl-CoA dehydrogenase genes are decreased in hearts of copper-deficient rats. J Nutr 130:2143-50 |
