Copper is a vital metal ion for sustaining life. Dietary and genetic disorders in copper metabolism and copper-implicated degenerative diseases provide striking evidence that optimal copper metabolism is a critical biological process. The mechanism underlying copper uptake and distribution has been an active research question;however, there are significant gaps in our understanding of the biosynthesis of cuproproteins. In particular, it is not known how copper-containing enzymes, such as ferroxidases, superoxide dismutase 3, lysyl oxidase, tyrosinase, and dopamine beta-hydroxylase, assemble copper cofactor(s) at the secretory pathway. This is an important problem because functional defects of these enzymes lead to serious disorders, including iron-deficiency anemia, cardiovascular disorders, cancer, and neuronal diseases. A successful attempt for identification of new genes involved in copper utilization revealed that an intracellular potassium-proton antiporter conserved in eukaryotes is a critical molecular factor for copper metabolism. Several lines of study indicate that potassium transport into the lumen of the cellular secretory pathway facilitates copper incorporation into ferroxidases. This exciting research progress has opened new avenues by which the mechanisms underlying the biosynthesis of functional ferroxidases and possibly other metalloproteins are better understood. Multi-disciplinary approaches using purified ferroxidases, mammalian cells, and mouse models will be employed to pursue the following specific aims: (1) Characterize the roles for potassium in copper and iron metabolism using a mouse strain where a secretory pathway potassium transporter is deleted;(2) Gain mechanistic insights into potassium-facilitated copper metallation of ferroxidases;(3) Define the modes of action and metal-responsive regulation of the potassium transporter;and (4) Determine the effects of potassium in the diet on copper and iron absorption and distribution. This proposed research is significant and innovative in that it (1) characterizes a new molecular factor involved in the metabolism of vital metal ions, copper, iron, and potassium;(2) discovers a novel functional role for potassium, a major intracellular cation;(3) gains better insights into the interactions among nutritional metal ions;and (4) would lead to the development of methods that facilitate absorption and distribution of copper, iron, and potassium. The outcomes of this project should have broad impacts on gaining mechanistic insights into metal metabolism, biosynthesis of metalloproteins, and combating various metal ion-related disorders, such as defects in normal growth and development, anemia, and metabolic and degenerative diseases.

Public Health Relevance

Copper is a mineral vital for sustaining life, yet it is toxic when misplaced or accumulated in excess. Copper levels in the diet and molecular factors involved in copper metabolism have been proposed as a therapeutic target. This project aims to gain mechanistic insights into copper absorption and utilization in the body to enhance our ability to combat various metal-related human diseases, such as anemia, metabolic and degenerative diseases, and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK079209-08
Application #
8700380
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
2007-07-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Nebraska Lincoln
Department
Biochemistry
Type
Earth Sciences/Resources
DUNS #
City
Lincoln
State
NE
Country
United States
Zip Code
68583
Wu, Xiaobin; Kim, Heejeong; Seravalli, Javier et al. (2016) Potassium and the K+/H+ Exchanger Kha1p Promote Binding of Copper to ApoFet3p Multi-copper Ferroxidase. J Biol Chem 291:9796-806
Bohovych, Iryna; Kastora, Stavroula; Christianson, Sara et al. (2016) Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses. Mol Cell Biol 36:2300-12
Hodgkinson, Victoria L; Zhu, Sha; Wang, Yanfang et al. (2015) Autonomous requirements of the Menkes disease protein in the nervous system. Am J Physiol Cell Physiol 309:C660-8
Hodgkinson, Victoria L; Dale, Jeffery M; Garcia, Michael L et al. (2015) X-linked spinal muscular atrophy in mice caused by autonomous loss of ATP7A in the motor neuron. J Pathol 236:241-50
Wei, Wenzhong; Smith, Nathan; Wu, Xiaobin et al. (2014) YCF1-mediated cadmium resistance in yeast is dependent on copper metabolism and antioxidant enzymes. Antioxid Redox Signal 21:1475-89
Frey, Avery G; Nandal, Anjali; Park, Jong Hwan et al. (2014) Iron chaperones PCBP1 and PCBP2 mediate the metallation of the dinuclear iron enzyme deoxyhypusine hydroxylase. Proc Natl Acad Sci U S A 111:8031-6
Massilamany, Chandirasegaran; Gangaplara, Arunakumar; Kim, Heejeong et al. (2013) Copper-zinc superoxide dismutase-deficient mice show increased susceptibility to experimental autoimmune encephalomyelitis induced with myelin oligodendrocyte glycoprotein 35-55. J Neuroimmunol 256:19-27
Kim, Heejeong; Wu, Xiaobin; Lee, Jaekwon (2013) SLC31 (CTR) family of copper transporters in health and disease. Mol Aspects Med 34:561-70
Ghosh, Manik C; Zhang, De-Liang; Jeong, Suh Young et al. (2013) Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α. Cell Metab 17:271-81
Gray, Lawrence W; Peng, Fangyu; Molloy, Shannon A et al. (2012) Urinary copper elevation in a mouse model of Wilson's disease is a regulated process to specifically decrease the hepatic copper load. PLoS One 7:e38327

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