Cagin 2015 Abstract MiP2015
|Nuclear adaptation to mitochondrial dysfunction.|
Mitochondrial DNA is a 16.6 kb double-stranded circular DNA molecule which can be found in various copy numbers in a tissue specific manner. mtDNA encodes for 37 genes whith only 13 of them being polypeptides, all having functions in oxidative phosphorylation. The rest of the proteins which have roles in mitochondria are encoded by nuclear genome. Therefore, controlled expression of both genomes (nuclear and mitochondrial) is a very important process for the well-being of the cell. Furthermore, mitochondria to nucleus cross-talk, also known as retrograde response, is conserved between species and can interact with most of the intracellular signaling pathways and processes .
Interaction between the two genomes of the cell is currently studied by depletion of mtDNA and one of the widely used models for studying effects of mtDNA depletion is rho-zero cells. Mammalian derived Rhoº cells were firstly characterized in 1989 by G. Attardi . We have decided to use mtDNA depleted cells in order to study details of nuclear involvement in mitochondrial dysfunction. Here, we use RNA sequencing strategy to compare nuclear gene expression induced by the complete depletion of mtDNA in cell lines of different origin.
Rhoº cells completely lack mtDNA, therefore they can not form respiratory chain complexes. As a result, these cells cannot synthesize ATP by OXPHOS and they are dependent on glycolysis. However, there are more consequences of complete depletion of mtDNA. For example, mitochondria of Rhoº cells are mostly fragmented compared to tubular/filamentous mitochondria observed in wild-type cells. Several microarray studies also showed that cellular transcriptome is changed upon mtDNA depletion. However, there is not a complete consensus on the current published results of other groups. This suggests that the details of retrograde response are complex and still waiting to be uncovered . We find common Rhoº transcriptomic signatures as well as particular modifications associated with the cellular origin.
We are currently performing detailed functional and bioinformatic analysis dissecting basis of common and cell specific responses. We strongly believe the outcome of this study can propose novel ways to treat mitochondrial diseases.
Labels: MiParea: mt-Membrane, mtDNA;mt-genetics, nDNA;cell genetics
Event: A1, Oral MiP2015
1-Cardiovascular Development Repair Dept, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; 2-Dept Bioquímica, Univ Zaragoza, Spain. - firstname.lastname@example.org
References and acknowledgements
- Butow RA, Avadhani NG (2004) Mitochondrial signaling: the retrograde response. Molecular Cell 14:1-15.
- King MP, Attardi G (1998) Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246:500-3.
- Cagin U, Enriquez JA (2015) The complex crosstalk between mitochondria and the nucleus: What goes in between? Int J Biochem Cell Biol doi:10.1016/j.biocel.2015.01.026.
The support of "Mitochondrial European Educational Training, MEET” project of the European Commission’s Seventh Framework Programme, FP7-PEOPLE-2012-ITN MARIE CURIE, grant agreement No. 317433 is gratefully acknowledged.