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HMGA1 proteins act as transcriptional regulators within the mitochondria and alter organelle related cellular function
Author(s) -
Dement Gregory Allan,
Reeves Raymond
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.lb63
Subject(s) - mitochondrion , mitochondrial dna , biology , microbiology and biotechnology , oxidative phosphorylation , mitochondrial fusion , gene , biochemistry
Recent findings from our lab placed the mammalian HMGA1 proteins into the complex milieu of the mitochondria. Consistent with their nuclear gene regulatory function, we demonstrated that in living cells the proteins associate with mitochondrial DNA at a particularly AT‐rich region called the regulatory D‐loop. In order to determine the biological ramifications of this result, we employed methods to analyze mitochondrial gene transcription, DNA replication, and overall organelle function. Real‐time PCR revealed that in transgenic MCF‐7 cells over‐expressing an HA‐tagged HMGA1 fusion protein, mitochondrial DNA (mtDNA) levels were reduced by 2‐fold relative to wild‐type MCF‐7 cells. Consistent with these reduced mtDNA levels, flow cytometric analysis revealed that mitochondrial mass was also reduced in HMGA1 over‐expressing cells. However, mitochondrial NADH Dehydrogenase 2 gene transcripts were found to be up‐regulated 4‐fold, suggesting that a transcriptional compensatory mechanism may be operating in mitochondria‐deficient cells. Nevertheless, compensation may be limited as cell survival studies showed an increased sensitivity of HMGA1 over‐expressing cells to treatment with the inhibitor of glycolysis, 2‐deoxy‐D‐glucose, indicating an overall deficiency in cellular oxidative phosphorylation. These observations are consistent with previously described cancer phenotypes and reveal possible mechanisms by which HMGA1 may affect tumor progression or other normal and disease related mitochondrial processes. Research supported by WSU Cancer Research Development Fund 17A‐2412‐0165 and NIH Grant RO1‐GM071760.