Transcriptomic analysis by array of reactivation of dihydroorotate dehydrogenase by respiration restores tumor growth of mitochondrial DNA-depleted cancer cells.
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Martina Bajzikova
PROVIDER: E-MTAB-6150 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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2016-10-21 | E-GEOD-77784 | biostudies-arrayexpress
Project description:Mitochondrial biogenesis is under the control of two different genetic systems: the nuclear genome (nDNA) and the mitochondrial genome (mtDNA). mtDNA is a circular genome of 16.6 kb encoding 13 of the approximately 90 subunits that form the respiratory chain, the remaining ones being encoded by the nuclear genome (nDNA). Eukaryotic cells are able to monitor and respond to changes in mitochondrial function through alterations in nuclear gene expression, a phenomenon first defined in yeast and known as retrograde regulation. With this experiment we aimed to identify the set of nuclear genes that significantly change their expression level in response to depletion of mtDNA. Experiment Overall Design: We used Affymetrix HG-U133A GeneChips to study the transcriptome of two human cell lines, 143BTK- and A549, which had been entirely depleted of mtDNA (rho0 cells), and compared it with the corresponding undepleted parental cells (rho+ cells). Three independent biological replicates were analyzed for each cell line and treatment group.
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Project description:The functional status of mitochondria is relayed by mitochondrial retrograde signaling (MRS) to elicit adaptive changes in nuclear gene expression. However, MRS pathways that sense the amount of the multi-copy mitochondrial DNA (mtDNA) in mammalian cells remain poorly understood. Budding yeast have “intergenomic signaling” pathways that can sense the amount of mtDNA independently of oxidative phosphorylation (OXPHOS), the primary function of genes encoded by mtDNA. We found that mtDNA-depleted IMR90 cells can sustain OXPHOS for a significant amount of time, providing a robust model system to interrogate human intergenomic signaling. FAM43A is induced early in response to mtDNA depletion in a CHK2 kinase-dependent manner, and its depletion activates CHK2 to increase mtDNA copy number via upregulation of the p53R2 form of ribonucleotide reductase. We propose that FAM43A serves a checkpoint-like function that restricts mtDNA replication in the presence of mtDNA stress to maintain mtDNA integrity. FAM43A could be a candidate mtDNA-disease locus and a therapeutic target for mtDNA depletion syndromes.
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| phs000339 | dbGaP
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