Abstract
BackgroundInteractions 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.ResultsCultured 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.ConclusionWe 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.
Highlights
Interactions between the gene products encoded by the mitochondrial and nuclear genomes play critical roles in eukaryotic cellular function
MtDNA-depleted cell lines possess distorted mitochondria-like structures comprised of nuclearencoded mitochondrial proteins [9,10,11] and demonstrate increased invasive behavior in culture [12,13,14,15,16,17] mitochondrial DNA (mtDNA)-depleted cells can grow as tumor xenografts in immune-deficient mice in some instances [18,19], but not others [20]
Antimycin A-treated A549 cells showed reduced oxygen consumption, while A549 ρ0 cells were not significantly affected by drug-treatment (Fig. 1B). These results strongly suggest that residual mitochondria-dependent aerobic respiration in A549 ρ0 cells, if present, is below the threshold that can be measured in this assay
Summary
Interactions between the gene products encoded by the mitochondrial and nuclear genomes play critical roles in eukaryotic cellular function. 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. Showhumanmask.do lists 870 human mitochondrial proteins encoded by the nuclear genome [5]. MtDNA-depleted cell lines possess distorted mitochondria-like structures comprised of nuclearencoded mitochondrial proteins [9,10,11] and demonstrate increased invasive behavior in culture [12,13,14,15,16,17] mtDNA-depleted cells can grow as tumor xenografts in immune-deficient mice in some instances [18,19], but not others [20]
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