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Molecular and Cellular Biology, October 2009, p. 5426-5440, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.00105-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

HMGA1 Levels Influence Mitochondrial Function and Mitochondrial DNA Repair Efficiency{triangledown} ,{dagger}

Li Mao,1 Kelsey J. Wertzler,1 Scott C. Maloney,2 Zeping Wang,1 Nancy S. Magnuson,1 and Raymond Reeves1*

School of Molecular Biosciences, Washington State University, Pullman, Washington 99164-4660,1 Kelley School of Business, Indiana University, 1275 E. Tenth Street, Bloomington, Indiana 474052

Received 22 January 2009/ Returned for modification 12 March 2009/ Accepted 24 July 2009

HMGA chromatin proteins, a family of gene regulatory factors found at only low concentrations in normal cells, are almost universally overexpressed in cancer cells. HMGA proteins are located in the nuclei of normal cells except during the late S/G2 phases of the cell cycle, when HMGA1, one of the members of the family, reversibly migrates to the mitochondria, where it binds to mitochondrial DNA (mtDNA). In many cancer cells, this controlled shuttling is lost and HMGA1 is found in mitochondria throughout the cell cycle. To investigate the effects of HMGA1 on mitochondria, we employed a genetically engineered line of human MCF-7 cells in which the levels of transgenic HMGA1 protein could be reversibly controlled. "Turn-ON" and "turn-OFF" time course experiments were performed with these cells to either increase or decrease intracellular HMGA1 levels, and various mitochondrial changes were monitored. Results demonstrated that changes in both mtDNA levels and mitochondrial mass inversely paralleled changes in HMGA1 concentrations, strongly implicating HMGA1 in the regulation of these parameters. Additionally, the level of cellular reactive oxygen species (ROS) increased and the efficiency of repair of oxidatively damaged mtDNA decreased as consequences of elevated HMGA1 expression. Increased ROS levels and reduced repair efficiency in HMGA1-overexpressing cells likely contribute to the increased occurrence of mutations in mtDNA frequently observed in cancer cells.

* Corresponding author. Mailing address: School of Molecular Biosciences, Washington State University, Biotechnology/Life Sciences Bldg., Rm. 143, Pullman, WA 99164-4660. Phone: (509) 335-1948. Fax: (509) 335-4159. E-mail: reevesr{at}mail.wsu.edu

{triangledown} Published ahead of print on 17 August 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, October 2009, p. 5426-5440, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.00105-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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