How do human cells react to the absence of mitochondrial DNA?

TitleHow do human cells react to the absence of mitochondrial DNA?
Publication TypeJournal Article
Year of Publication2009
AuthorsMineri, R, Pavelka, N, Fernandez-Vizarra, E, Ricciardi-Castagnoli, P, Zeviani, M, Tiranti, V
JournalPLoS One
Volume4
Issue5
Paginatione5713
Date Published2009 May 28
ISSN1932-6203
KeywordsBlotting, Western, Cell Cycle, Cell Line, Cell Proliferation, DNA, Mitochondrial, Down-Regulation, Electron Transport Complex III, Gene Expression Profiling, Humans, Mitochondria, Neoplasm Proteins, Oligonucleotide Array Sequence Analysis, Protein Transport, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger
Abstract

BACKGROUND: Mitochondrial biogenesis is under the control of two different genetic systems: the nuclear genome (nDNA) and the mitochondrial genome (mtDNA). The 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 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. To investigate how the cellular transcriptome is modified in response to the absence of mtDNA, we used Affymetrix HG-U133A GeneChip arrays to study the gene expression profile of two human cell lines, 143BTK(-) and A549, which had been entirely depleted of mtDNA (rho(o) cells), and compared it with that of corresponding undepleted parental cells (rho(+) cells).RESULTS: Our data indicate that absence of mtDNA is associated with: i) a down-regulation of cell cycle control genes and a reduction of cell replication rate, ii) a down-regulation of nuclear-encoded subunits of complex III of the respiratory chain and iii) a down-regulation of a gene described as the human homolog of ELAC2 of E. coli, which encodes a protein that we show to also target to the mitochondrial compartment.CONCLUSIONS: Our results indicate a strong correlation between mitochondrial biogenesis and cell cycle control and suggest that some proteins could have a double role: for instance in controlling both cell cycle progression and mitochondrial functions. In addition, the finding that ELAC2 and maybe other transcripts that are located into mitochondria, are down-regulated in rho(o) cells, make them good candidates for human disorders associated with defective replication and expression of mtDNA.

DOI10.1371/journal.pone.0005713
Alternate JournalPLoS ONE
Citation Key10.1371/journal.pone.0005713
PubMed ID19492094
PubMed Central IDPMC2683933
Grant ListGGP07019 / / Telethon / Italy