Open Access Highly Accessed Research article

mtDNA depletion confers specific gene expression profiles in human cells grown in culture and in xenograft

Darren Magda1, Philip Lecane1, Julia Prescott1, Patricia Thiemann1, Xuan Ma1, Patricia K Dranchak2, Donna M Toleno2, Krishna Ramaswamy2, Kimberly D Siegmund3 and Joseph G Hacia2*

Author Affiliations

1 Pharmacyclics Inc., 995 East Arques Avenue, Sunnyvale, CA, 94085, USA

2 Department of Biochemistry and Molecular Biology, University of Southern California, 2250 Alcazar Street, IGM 240, Los Angeles, CA, 90089, USA

3 Department of Preventive Medicine, University of Southern California, Los Angeles, CA, 90089, USA

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BMC Genomics 2008, 9:521  doi:10.1186/1471-2164-9-521

Published: 3 November 2008

Abstract

Background

Interactions between the gene products encoded by the mitochondrial and nuclear genomes play critical roles in eukaryotic cellular function. However, the effects mitochondrial DNA (mtDNA) levels have on the nuclear transcriptome have not been defined under physiological conditions. In order to address this issue, we characterized the gene expression profiles of A549 lung cancer cells and their mtDNA-depleted ρ0 counterparts grown in culture and as tumor xenografts in immune-deficient mice.

Results

Cultured A549 ρ0 cells were respiration-deficient and showed enhanced levels of transcripts relevant to metal homeostasis, initiation of the epithelial-mesenchymal transition, and glucuronidation pathways. Several well-established HIF-regulated transcripts showed increased or decreased abundance relative to the parental cell line. Furthermore, growth in culture versus xenograft has a significantly greater influence on expression profiles, including transcripts involved in mitochondrial structure and both aerobic and anaerobic energy metabolism. However, both in vitro and in vivo, mtDNA levels explained the majority of the variance observed in the expression of transcripts in glucuronidation, tRNA synthetase, and immune surveillance related pathways. mtDNA levels in A549 xenografts also affected the expression of genes, such as AMACR and PHYH, involved in peroxisomal lipid metabolic pathways.

Conclusion

We have identified mtDNA-dependent gene expression profiles that are shared in cultured cells and in xenografts. These profiles indicate that mtDNA-depleted cells could provide informative model systems for the testing the efficacy of select classes of therapeutics, such as anti-angiogenesis agents. Furthermore, mtDNA-depleted cells grown culture and in xenografts provide a powerful means to investigate possible relationships between mitochondrial activity and gene expression profiles in normal and pathological cells.