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B01 - Oxidative stress signalling in lifespan regulation

Aleksandra Trifunovic
CECAD Forschungszentrum/Institut für Mitochondriale Erkrankungen und Alterung
Universitätsklinikum Köln

E-mail: aleksandra.trifunovicSpamProtectionuk-koeln.de
Phone: +49 - 221 / 478 84291
For more information and contact please visit the TRIFUNOVIC LAB.

Abstract

Increased ROS production has been detected in a number of long-lived mitochondrial mutants leading to the hypothesis that ROS may be a lifespan-promoting signal, which transduce inputs from the mitochondria to other compartments of the cell. However, molecular mechanisms and signalling steps behind this process are largely unknown. We recently identified a transcription factor that mediates a hormetic response to increased ROS triggering mitochondria-induced longevity. Based on these findings we aim to dissect ROS signalling initiated in mitochondria by analysing downstream and upstream factors through genetic screens and functional analysis of candidate proteins.

Project-related publications

Herholz, M., Cepeda, E., Baumann, L., Kukat, A., Hermeling, J., Maciej, S., Szczepanowska, K., Pavlenko, V., Frommolt, P., and Trifunovic, A. (2019). KLF-1 orchestrates a xenobiotic detoxification program essential for longevity of mitochondrial mutants. Nat. Commun. 10, 3323. DOI: 10.1038/s41467-019-11275-w. 

Becker, C., Kukat, A., Szczepanowska, K., Hermans, S., Senft, K., Brandscheid, C.P., Maiti, P., and Trifunovic, A. (2018). CLPP deficiency protects against metabolic syndrome but hinders adaptive thermogenesis. EMBO Rep. 19, e45126.

Seiferling, D., Szczepanowska, K., Becker, C., Senft, K., Hermans, S., Maiti, P., König, T., Kukat, A., Trifunovic, A. (2016). Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt. EMBO Rep. 17, 953-964.

Guarás, A., Perales-Clemente, E., Calvo, E., Acín-Pérez, R., Loureiro-Lopez, M., Pujol, C., Martínez-Carrascoso, I., Nuñez, E., García-Marqués, F., Rodríguez-Hernández, M.A., Cortés, A., Diaz, F., Pérez-Martos, A., Moraes, C.T., Fernández-Silva, P., Trifunovic, A., Navas, P., Vazquez, J., Enríquez, J.A. (2016). The CoQH2/CoQ ratio serves as a sensor of respiratory chain efficiency. Cell Rep. 15, 197-209.

Szczepanowska, K., Maiti, P., Kukat, A., Hofsetz, E., Nolte, H., Senft, K., Becker, C., Ruzzenente, B., Hornig-Do, H.-T., Wibom, R., Wiesner, R.J., Krüger, M. and Trifunovic, A. (2016). CLPP coordinates mitoribosomal assembly through regulation of ERAL1 levels. EMBO J. 35, 2566-2583.

Pujol, C., Bratic-Hench, I., Sumakovic, M., Hench, J., Mourier, A., Baumann, L., Pavlenko, V., and Trifunovic, A. (2013). Succinate dehydrogenase upregulation destabilize complex I and limits the lifespan of gas-1 mutant. PLoS One 8, e59493.

Ahlqvist, K.J., Hamalainen, R.H., Yatsuga, S., Uutela, M., Terzioglu, M., Gotz, A., Forsstrom, S., Salven, P., Angers-Loustau, A., Kopra, O.H., Tyynismaa, H., Larsson, N.G., Wartiovaara, K., Prolla, T., Trifunovic, A., and Suomalainen, A. (2012). Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. Cell Metab. 15, 100-109.

Hench, J., Bratic Hench, I., Pujol, C., Ipsen, S., Brodesser, S., Mourier, A., Tolnay, M., Frank, S., and Trifunovic, A. (2011). A tissue-specific approach to the analysis of metabolic changes in Caenorhabditis elegans. PLoS One 6, e28417.

Bratic, I., Hench, J., Henriksson, J., Antebi, A., Burglin, T.R., and Trifunovic, A. (2009). Mitochondrial DNA level, but not active replicase, is essential for Caenorhabditis elegans development. Nucleic Acids Res. 37, 1817-1828.

Trifunovic, A., Hansson, A., Wredenberg, A., Rovio, A.T., Dufour, E., Khvorostov, I., Spelbrink, J.N., Wibom, R., Jacobs, H.T., and Larsson, N.G. (2005). Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc. Natl. Acad. Sci. U. S. A. 102, 17993-17998.

Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J.N., Rovio, A.T., Bruder, C.E., Bohlooly, Y.M., Gidlof, S., Oldfors, A., Wibom, R., Tornell, J., Jacobs, H.T., and Larsson, N.G. (2004). Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417-423.