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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

Peker, E., Weiss, K., Song, J., Zarges, C., Gerlich, S., Boehm, V., Trifunovic, A., Langer, T., Gehring, N., Becker, T. and Riemer, J. (2023). A two-step mitochondrial import pathway couples the disulfide relay with matrix complex I biogenesis. J. Cell Biol. 222, e202210019.

Montoro-Gámez, C., Nolte, H., Molinié, T., Evangelista, G., Tröder, S., Barth, E., Popovic, M., Trifunovic, A., Zevnik, B., Langer, T., Rugarli E.I. (2023). SARM1 deletion delays cerebellar but not spinal cord degeneration in an enhanced mouse model of SPG7 deficiency. Brain. 2023 Apr 22:awad136. doi: 10.1093/brain/awad136. Online ahead of print. PMID: 37086482

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

Ravanelli, S., Li, Q., Annibal, A., Trifunovic, A., Antebi, A., Hoppe, T. (2022). Reprograming of proteasomal degradation by branched chain amino acid metabolism.  Aging Cell 2022, https://doi.org/10.1111/acel.13725

Salscheider, S.L., Gerlich, S., Cabrera-Orefice, A., Peker, E., Rothemann, R.A., Murschall, L.M., Finger, Y., Szczepanowska, K., Ahmadi, Z. A., Guerrero-Castillo, S. Erdogan, A., Becker, M. Ali, M., Habich, M., Petrungaro, C., Burdina, N., Schwarz, G., Klußmann, M., Neundorf, I., Stroud, D.A., Ryan, M.T., Trifunovic, A., Brandt, U., and Riemer, J. (2022). AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5. EMBO Journal, 41, e110784.

Schatton, D., Di Pietro, G., Szczepanowska, K., Veronese, M., Marx, M.-C., Braunöhler, K., Esther, B., Müller, S., Giavalisco, P., Langer, T., Trifunovic, A., Rugarli, I.E. (2022). CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression. Elife. 2022 May 13;11:e74552. DOI: 10.7554/eLife.74552

Croon, M., Szczepanowska, K., Popovic, M., Lienkamp, C., Senft, K., Brandscheid, C.P., Bock, T., Gnatzy-Feik, L., Ashurov, A., Acton, R.J., Kaul, H., Pujol, C., Rosenkranz, S., Krüger, M., Trifunovic, A. (2022). FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction. Sci Adv. 2022 Apr 8;8(14):eabn7105

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

Hoehne, M.N., Jacobs, L.J.H.C., Lapacz, K.J., Calabrese, G., Murschall, L.M., Marker, T., Kaul, H., Trifunovic, A., Morgan, B., Fricker, M., Belousov, V.V., Riemer J. (2022). Spatial and temporal control of mitochondrial H2O2 release in intact human cells. EMBO J, e109169

Willenborg, S., Sanin, D.E., Jais, A., Ding, X., Ulas, T., Nüchel, J., Popović, M., MacVicar, T., Langer, T., Schultze, J.L., Gerbaulet, A., Roers, A., Pearce, E.J., Brüning, J.C., Trifunovic, A., Eming, S.A. (2021). Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing.  Cell Metabolism (2021), https://doi.org/10.1016/j.cmet.2021.10.004

Bock, T., Türk, C., Aravamudhan, S., Keufgens, L., Bloch, W., Rozsivalova, D.H., Romanello, V., Nogara, L., Blaauw, B., Trifunovic, A., Braun, T., Krüger, M. (2021). PERM1 interacts with the MICOS-MIB complex to connect the mitochondria and sarcolemma via ankyrin B. Nat Commun. 2021 Aug 12;12(1):4900

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

Szczepanowska, K., Trifunovic, A. (2021). "Mitochondrial matrix proteases: quality control and beyond. " FEBS J. 2021 May 10

Aravamudhan, S., Türk, C., Bock, T., Keufgens, L., Nolte, H., Lang, F., Krishnan, R.K., König, T., Hammerschmidt, P., Schindler, N., Brodesser, S., Rozsivalova, D.H., Rugarli, E., Trifunovic, A., Brüning, J., Langer, T., Braun, T., Krüger, M. (2021). Phosphoproteomics of the developing heart identifies PERM1 - An outer mitochondrial membrane protein.  2021 Feb 5;154:41-59. doi.org/10.1016/j.yjmcc.2021.01.010

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.

Timper, K., del Río-Martín, A., Cremer, A.L., Bremser, S., Alber, J. Giavalisco, P. Varela, L., Heilinger, C., Nolte, H., Trifunovic, A. Horvath, T.L., Kloppenburg, P., Backes, H. Brüning, J.C.  (2020). GLP-1 Receptor Signaling in Astrocytes Regulates Fatty Acid Oxidation, Mitochondrial Integrity, and Function. Cell Metab. S1550-4131(20)30240-0. doi: 10.1016/j.cmet.2020.05.001. 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.

Ricke, K.M., Paß, T., Kimoloi, S., Fährmann, K., Jüngst, C., Schauss, A., Baris, O.R., Aradjanski, M., Trifunovic, A., Eriksson Faelker, T.M., Bergami, M., Wiesner, R.J. (2020). Mitochondrial Dysfunction Combined with High Calcium Load Leads to Impaired Antioxidant Defense Underlying the Selective Loss of Nigral Dopaminergic Neurons. J Neurosci. 2020 Feb 26;40(9):1975-1986

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.