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Title: Nuclear HMGA1 nonhistone chromatin proteins directly influence mitochondrial transcription, maintenance, and function

Abstract

We have previously demonstrated that HMGA1 proteins translocate from the nucleus to mitochondria and bind to mitochondrial DNA (mtDNA) at the D-loop control region [G.A. Dement, N.R. Treff, N.S. Magnuson, V. Franceschi, R. Reeves, Dynamic mitochondrial localization of nuclear transcription factor HMGA1, Exp. Cell Res. 307 (2005) 388-401.] [11]. To elucidate possible physiological roles for such binding, we employed methods to analyze mtDNA transcription, mitochondrial maintenance, and other organelle functions in transgenic human MCF-7 cells (HA7C) induced to over-express an HA-tagged HMGA1 protein and control (parental) MCF-7 cells. Quantitative real-time (RT) PCR analyses demonstrated that mtDNA levels were reduced approximately 2-fold in HMGA1 over-expressing HA7C cells and flow cytometric analyses further revealed that mitochondrial mass was significantly reduced in these cells. Cellular ATP levels were also reduced in HA7C cells and survival studies showed an increased sensitivity to killing by 2-deoxy-D-glucose, a glycolysis-specific inhibitor. Flow cytometric analyses revealed additional mitochondrial abnormalities in HA7C cells that are consistent with a cancerous phenotype: namely, increased reactive oxygen species (ROS) and increased mitochondrial membrane potential ({delta}{psi}{sub m}). Additional RT-PCR analyses demonstrated that gene transcripts from both the heavy (ND2, COXI, ATP6) and light (ND6) strands of mtDNA were up-regulated approximately 3-fold in HA7Cmore » cells. Together, these mitochondrial changes are consistent with many previous reports and reveal several possible mechanisms by which HMGA1 over-expression, a common feature of naturally occurring cancers, may affect tumor progression.« less

Authors:
 [1];  [1];  [2]
  1. School of Molecular Biosciences, Washington State University, Rm. 639, Fulmer Hall, Pullman, WA 99164-4660 (United States)
  2. School of Molecular Biosciences, Washington State University, Rm. 639, Fulmer Hall, Pullman, WA 99164-4660 (United States). E-mail: reevesr@mail.wsu.edu
Publication Date:
OSTI Identifier:
20858067
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 313; Journal Issue: 1; Other Information: DOI: 10.1016/j.yexcr.2006.09.014; PII: S0014-4827(06)00399-5; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ATP; CHROMATIN; GLUCOSE; GLYCOLYSIS; MITOCHONDRIA; OXIDASES; OXYGEN; PHENOTYPE; PHOSPHORYLATION; POLYMERASE CHAIN REACTION; TRANSCRIPTION; TRANSCRIPTION FACTORS

Citation Formats

Dement, Gregory A., Maloney, Scott C., and Reeves, Raymond. Nuclear HMGA1 nonhistone chromatin proteins directly influence mitochondrial transcription, maintenance, and function. United States: N. p., 2007. Web. doi:10.1016/j.yexcr.2006.09.014.
Dement, Gregory A., Maloney, Scott C., & Reeves, Raymond. Nuclear HMGA1 nonhistone chromatin proteins directly influence mitochondrial transcription, maintenance, and function. United States. doi:10.1016/j.yexcr.2006.09.014.
Dement, Gregory A., Maloney, Scott C., and Reeves, Raymond. Mon . "Nuclear HMGA1 nonhistone chromatin proteins directly influence mitochondrial transcription, maintenance, and function". United States. doi:10.1016/j.yexcr.2006.09.014.
@article{osti_20858067,
title = {Nuclear HMGA1 nonhistone chromatin proteins directly influence mitochondrial transcription, maintenance, and function},
author = {Dement, Gregory A. and Maloney, Scott C. and Reeves, Raymond},
abstractNote = {We have previously demonstrated that HMGA1 proteins translocate from the nucleus to mitochondria and bind to mitochondrial DNA (mtDNA) at the D-loop control region [G.A. Dement, N.R. Treff, N.S. Magnuson, V. Franceschi, R. Reeves, Dynamic mitochondrial localization of nuclear transcription factor HMGA1, Exp. Cell Res. 307 (2005) 388-401.] [11]. To elucidate possible physiological roles for such binding, we employed methods to analyze mtDNA transcription, mitochondrial maintenance, and other organelle functions in transgenic human MCF-7 cells (HA7C) induced to over-express an HA-tagged HMGA1 protein and control (parental) MCF-7 cells. Quantitative real-time (RT) PCR analyses demonstrated that mtDNA levels were reduced approximately 2-fold in HMGA1 over-expressing HA7C cells and flow cytometric analyses further revealed that mitochondrial mass was significantly reduced in these cells. Cellular ATP levels were also reduced in HA7C cells and survival studies showed an increased sensitivity to killing by 2-deoxy-D-glucose, a glycolysis-specific inhibitor. Flow cytometric analyses revealed additional mitochondrial abnormalities in HA7C cells that are consistent with a cancerous phenotype: namely, increased reactive oxygen species (ROS) and increased mitochondrial membrane potential ({delta}{psi}{sub m}). Additional RT-PCR analyses demonstrated that gene transcripts from both the heavy (ND2, COXI, ATP6) and light (ND6) strands of mtDNA were up-regulated approximately 3-fold in HA7C cells. Together, these mitochondrial changes are consistent with many previous reports and reveal several possible mechanisms by which HMGA1 over-expression, a common feature of naturally occurring cancers, may affect tumor progression.},
doi = {10.1016/j.yexcr.2006.09.014},
journal = {Experimental Cell Research},
number = 1,
volume = 313,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}