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Title: Developmental regulation of mitochondrial biogenesis and function in the mouse mammary gland during a prolonged lactation cycle

Author
item HADSELL, DARRYL - Children'S Nutrition Research Center (CNRC)
item OLEA, WALTER - Children'S Nutrition Research Center (CNRC)
item WEI, JERRY - Children'S Nutrition Research Center (CNRC)
item FIOROTTO, MARTA - Children'S Nutrition Research Center (CNRC)
item MATSUNAMI, RISE - Texas Heart Institute
item ENGLER, DAVID - Texas Heart Institute
item COLLIER, ROBERT - University Of Arizona

Submitted to: Physiological Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/23/2010
Publication Date: 3/29/2011
Citation: Hadsell, D.L., Olea, W., Wei, J., Fiorotto, M.L., Matsunami, R.K., Engler, D.A., Collier, R.J. 2011. Developmental regulation of mitochondrial biogenesis and function in the mouse mammary gland during a prolonged lactation cycle. Physiological Genomics. 43(6):271-285.

Interpretive Summary: In this study we compared changes in mammary cell mitochondrial function over the course of a lactation with changes in the mitochondrial proteome. By using a high-throughput technique, we were able to measure changes in over 250 proteins in the mitochondrial. Through this approach we identified changes in metabolic pathways that were linked to specific regulatory molecules that could have importance to determining the ability of mitochondrial to support milk synthesis. These molecules could have a major impact on milk production.

Technical Abstract: The regulation of mitochondrial biogenesis and function in the lactating mammary cell is poorly understood. The goal of this study was to use proteomics to relate temporal changes in mammary cell mitochondrial function during lactation to changes in the proteins that make up this organelle. The hypothesis tested was that changes in mammary cell mitochondrial biogenesis and function during lactation would be accounted for by coordinated changes in the proteins of the electron transport chain and that some of these proteins might be linked by their expression patterns to PPARGC1alpha and AMP kinase. The mitochondrial proteome was studied along with markers of mitochondrial biogenesis and function in mammary tissue collected from mice over the course of a single prolonged lactation cycle. Mammary tissue concentrations of AMP and ADP were increased ("P" < 0.05) during early lactation and then declined with prolonged lactation. Similar changes were also observed for mitochondrial ATP synthesis activity, mitochondrial mass and DNA copy number. Analysis of the mammary cell mitochondrial proteome identified 244 unique proteins. Of these, only two proteins of the electron transport chain were found to increase during early lactation. In contrast, coordinated changes in numerous electron transport chain proteins were observed both during mid- and late lactation. There were six proteins that could be directly linked to PPARGC1alpha through network analysis. Abundance of PPARGC-1alpha and phosphorylation of AMP kinase was highest on "day" 2 postpartum. The results suggest that the increases in mammary mitochondria ATP synthesis activity during early lactation results from changes in only a limited number proteins. In addition, decreases in a handful of proteins linked to lipid oxidation could be temporally linked to decreases in PPARGC1alpha and phospho-AMP kinase suggesting potential roles for these proteins in coordinating mammary gland metabolism during early lactation.