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B01 | Oxidative stress signalling and lipid metabolism in lifespan regulation

Aleksandra Trifunovic
CECAD Research Center/Institute for Mitochondrial Diseases and Ageing
University Hospital Cologne

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

Running time within the CRC 1218: 07/2016 - 06/2024.


Increasing body of evidence indicate that at moderate concentrations, ROS acts as a second messenger that regulates a number of signalling pathways. We identified a redox-regulated transcription factor KLF-1 as a mediator of a cytoprotective response that dictates longevity induced by reduced mitochondrial function. In particular we identified KLF-1 mediated regulation of peroxisomal lipid metabolism as essential for longevity assurance in mitochondrial that we intend to address in the second funding period. 

Project-related publications

Hermeling, J. CW., Herholz, M., Baumann, L., Cores, E.C., Zečić, A., Hoppe, T., Riemer, J., Trifunovic, A. (2022). Mitochondria-originated redox signalling regulates KLF-1 to promote longevity in Caenorhabditis elegans. Redox Biology 2022,  https://doi.org/10.1016/j.redox.2022.102533

Rumyantseva, A., Popovic, M., Trifunovic, A. (2022). CLPP deficiency ameliorates neurodegeneration caused by impaired mitochondrial protein synthesis. Brain (Oxford Academic) awab303, https://doi.org/10.1093/brain/awab303

Kaspar S., Oertlin C., Szczepanowska K., Kukat A., Senft K., Lucas C., Brodesser S., Hatzoglou M., Larsson O., Topisirovic I., Trifunovic A. (2021)
Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR
Science Advances  26 May 2021: Vol. 7, no. 22, eabf0971; DOI: 10.1126/sciadv.abf0971

Rumyantseva, A., Motori, E., Trufunovic, A. (2020). DARS2 is indispensable for Purkinje cell survival and protects against cerebellar ataxia". Hum Mol Genet.; 2020 Oct 10;29(17):2845-2854. DOI: 10.1093/hmg/ddaa176.

Hofsetz, E., Demir, F., Szczepanowska, K., Kukat, A., Kizhakkedathu, J., Trifunovic, A., Huesgen, P.F. (2020). The Mouse Heart Mitochondria N Terminome Provides Insights Into ClpXP-mediated Proteolysis. Mol Cell Proteomics;mcp.RA120.002082. DOI: 10.1074/mcp.RA120.002082. Online ahead of print.

Szczepanowska, K., Senft, K., Heidler, J., Herholz, M., Kukat, M.A., Höhne, N., Hofsetz, E., Becker, C.,  Kaspar, S., Giese, H., Zwicker, K., Guerrero-Castillo, S, Baumann, L., Kauppila, J., Rumyantseva, A., Müller, S., Frese, C.K., Brandt, U., Riemer, J., Wittig, I., and Trifunovic, A. (2020) A salvage pathway maintains highly functional respiratory complex I. Nature Communications 11, 1643.

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.