Karolina Szczepanowska, PhD
Laboratory of Metabolic Quality Control
Metabolism is firmly defined by the mitochondria. They dictate the bioenergetic capacity of our cells and provide us with critical metabolites. The bulk of cellular energy is generated by the elaborative molecular machines embedded inside the mitochondrial membranes, jointly known as the OXPHOS system. The everyday stress impacts the composition and functionality of OXPHOS, leading to its dysfunction. Consequently, compromised OXPHOS fitness has been implicated in a broad spectrum of disorders, including cancer, diabetes, obesity, ischemia-reperfusion injury, neurodegeneration, or aging.
What are the mechanisms that sculpture OXPHOS in response to challenges? Is there a way to repair it when injured by stress? We recently started to recognize that mitochondrial bioenergetics stays under the constant surveillance of dedicated proteostatic machinery. Yet, the exact mechanisms and responsible players remain mostly elusive.
Our research aims to dissect the mechanisms that mediate the quality control of OXPHOS exposed to disease-associated conditions and trace the molecular signals that steer its degradation. With the help of modern proteomics and advanced biochemical and molecular biology approaches, we discover the damage hot-spots in mammalian mitochondria and identify the factors responsible for their recognition and repair.
Our findings will help to understand how metabolic quality control contributes to the known cellular stress-responses. Furthermore, OXPHOS salvage can constitute an attractive target for novel therapies against a broad range of human diseases.
Chojnacka KJ, Elancheliyan P, Mussulini BHM, Mohanraj K, Callegari S, Gosk A, Banach T, Góral T, Szczepanowska K, Rehling P, Serwa RA, Chacińska A. Ovarian carcinoma immunoreactive antigen-like protein 2 (OCIAD2) is a novel complex III specific assembly factor in mitochondria. Mol Biol Cell. 2022 Jan 26: mbcE21030143. doi: 10.1091/mbc.E21-03-0143.
Szczepanowska K*, Trifunovic A*. Mitochondrial matrix proteases: quality control and beyond. FEBS J. 2021 May 10. doi: 10.1111/febs.15964.
Szczepanowska K*, Trifunovic A*. Tune instead of destroy: How proteolysis keeps OXPHOS in shape. Biochim Biophys Acta Bioenerg. 2021 Jan 6;1862(4):148365. doi: 10.1016/j.bbabio.2020.148365
Kaspar S, Oertlin C, Szczepanowska K, Kukat A, Senft K, Lucas C, Brodesser S, Hatzoglou M, Larsson O, Topisirovic I, Trifunovic A. Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR. Sci Adv. 2021 May 26;7(22): eabf0971. doi: 10.1126/sciadv.abf0971.
Meßner M, Mandl MM, Hackl MW, Reinhardt T, Ardelt MA, Szczepanowska K, Frädrich JE, Waschke J, Jeremias I, Fux A, Stahl M, Vollmar AM, Sieber SA, Pachmayr J. Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers. Sci Rep. 2021 May 27;11(1):11185. doi: 10.1038/s41598-021-90801-7.
Szczepanowska K*, Senft K, Heidler J, Herholz M, Kukat A, Höhne MN, Hofsetz E, Becker C, Kaspar S, Giese H, Zwicker K, Guerrero-Castillo S, Baumann L, Kauppila J, Rumyantseva A, Müller S, Frese CK, Brandt U, Riemer J, Wittig I, Trifunovic A.* A salvage pathway maintains highly functional respiratory complex I. Nature Communications 2020 Apr 2;11(1):1643. doi: 10.1038/s41467-020-15467-7.
Hofsetz E, Demir F, Szczepanowska K, Kukat A, Kizhakkedathu JN, Trifunovic A, Huesgen PF. The Mouse Heart Mitochondria N Terminome Provides Insights into ClpXP-Mediated Proteolysis. Mol Cell Proteomics. 2020 Aug;19(8):1330-1345. doi: 10.1074/mcp.RA120.002082.
Szczepanowska K*, Trifunovic A*. Mitochondrial DNA and aging. The Human Mitochondrial Genome. From basic biology to disease. Edited by Giuseppe Gasparre and Anna Maria Porcelli; 2020;
Herholz M, Cepeda E, Baumann L, Kukat A, Hermeling J, Maciej S, Szczepanowska K, Pavlenko V, Frommolt P, Trifunovic A. KLF-1 orchestrates a xenobiotic detoxification program essential for longevity of mitochondrial mutants. Nature Communications. 2019 Jul 25;10(1):3323. doi: 10.1038/s41467-019-11275-w.
Becker C, Kukat A, Szczepanowska K, Hermans S, Senft K, Brandscheid CP, Maiti P, Trifunovic A. CLPP deficiency protects against metabolic syndrome but hinders adaptive thermogenesis. EMBO Rep. 2018 May;19(5):e45126. doi: 10.15252/embr.201745126.
Szczepanowska K, Trifunovic A. Origins of mtDNA mutations in ageing. Essays Biochem. 2017 Jul 11;61(3):325-337. doi: 10.1042/EBC20160090.
Szczepanowska K, Maiti P, Kukat A, Hofsetz E, Nolte H, Senft K, Becker C, Ruzzenente B, Hornig-Do HT, Wibom R, Wiesner RJ, Krüger M, Trifunovic A. CLPP coordinates mitoribosomal assembly through the regulation of ERAL1 levels. EMBO J. 2016 Dec 1;35(23):2566-2583. doi: 10.15252/embj.201694253.
Seiferling D, Szczepanowska K, Becker C, Senft K, Hermans S, Maiti P, König T, Kukat A, Trifunovic A. Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt. EMBO Rep. 2016 Jul;17(7):953-64. doi: 10.15252/embr.201642077.
Islam MS, Nolte H, Jacob W, Ziegler AB, Pütz S, Grosjean Y, Szczepanowska K, Trifunovic A, Braun T, Heumann H, Heumann R, Hovemann B, Moore DJ, Krüger M. Human R1441C LRRK2 regulates the synaptic vesicle proteome and phosphoproteome in a Drosophila model of Parkinson's disease. Hum Mol Genet. 2016 Dec 15;25(24):5365-5382. doi: 10.1093/hmg/ddw352.
Szczepanowska K, Trifunovic A. Different faces of mitochondrial DNA mutators. Biochim Biophys Acta. 2015 Nov;1847(11):1362-72. doi: 10.1016/j.bbabio.2015.05.016.
Foury F, Szczepanowska K. Antimutator alleles of yeast DNA polymerase gamma modulate the balance between DNA synthesis and excision. PLoS One. 2011;6(11):e27847. doi: 10.1371/journal.pone.0027847.
Szczepanowska K, Foury F. A cluster of pathogenic mutations in the 3'-5' exonuclease domain of DNA polymerase gamma defines a novel module coupling DNA synthesis and degradation. Hum Mol Genet. 2010 Sep 15;19(18):3516-29. doi: 10.1093/hmg/ddq267.
* As a co-corresponding author.
ABOUT GROUP LEADER
Dr. Karolina Szczepanowska completed her Ph.D. in 2011 under the supervision of Francoise Foury at the University of Louvain, where she studied the mechanism entangled in mitochondrial genome maintenance. Next, she joined the lab of Aleksandra Trifunovic at the University of Cologne and Cluster of Excellence Cellular Stress Responses in Aging-Associated Disease. Her postdoctoral research focused on dissecting the secrets of mitochondrial protein homeostasis and quality control in mice, tissue cultures, and worms using advanced proteomic and biochemical approaches. In 2021 she established her research group at the ReMedy/IMol PAS.
SONATA BIS (Proline metabolism as a novel therapeutic target in diseases associated with mitochondrial dysfunction), National Science Center, 4 240 080 PLN, principal investigator
EMBO Installation Grant (IG 5040: The OXPHOS quality control in cancer), principal investigator
PASIFIC Grant (MetaboSentinels 66830), Polish Academy of Sciences, Maria Sklodowska-Curie Actions, 855 670 PLN, principal investigator
CMMC Individual Project Funding Program, Center for Molecular Medicine Cologne, Germany, co-applicant
Advanced Postdoc Grant, CRC/SFB1218, Cologne, Germany, 25 000 EUR, principal investigator
CECAD Travel Grant
Professorinnenprogramme - 3rd Female Scientists Support Program, University of Cologne, Germany
FEBS Travel Grant
Ph.D. Research Grant, Fonds pour la Formation à la Recherche dans l’Industrie et l’Agriculture, Brussels, Belgium
Erasmus Research Project Fellowship, University Louvain, Belgium
Dream profession of your childhood?
As a 3rd-grader, I made an odd (but super official) statement to my family that I will become a scientist one day. Then I followed.
Your dream profession - now?
Here I am.
What melody do you hum when working in the lab?
Not much. I am busy enough talking to my students (and to myself!).
Your favourite joke about scientists?
Girls can’t STEM.