Laboratorium Biogenezy Mitochondriów

Mitochondria pełnią kluczową rolę w metabolizmie oraz procesach regulacyjnych komórki. Mitochondria są niezbędne do życia każdej komórki eukariotycznej począwszy od organizmów jednokomórkowych do ssaków.

W skład mitochondriów wchodzi od 1000 do 1500 białek komórkowych, które syntetyzowane są w cytozolu, poza mitochondrium.

Biogeneza mitochondriów jest zależna od wydajnego importu, sortowania i dojrzewania białek, za które odpowiedzialne są wysoce konserwatywne translokazy białkowe i inne złożone szlaki biologiczne. Nasze badania mają na celu powiązanie procesu transportu z procesami regulującymi homeostazę białek mitochondrialnych. Postawiona przez nas hipoteza badawcza zakłada istnienie mechanizmu wymiany informacji między cytozolem a mitochondrium, który zaangażowany jest w biogenezę białek.

Celem naszych badań jest dogłębne zrozumienie złożonych i dynamicznych procesów związanych z biogenezą mitochondriów jak również utrzymaniem homeostazy białkowej komórek oraz zaburzeniami, które skutkują patologiami.

Chętnie podejmiemy współpracę z wysoce zmotywowanymi i wykwalifikowanymi studentami i doktorantami. Zapraszamy do kontaktu: a.chacinska@cent.uw.edu.pl

Group Leader:

Alumni:
dr Anna Antosiewicz
dr Arianna Barchesi
mgr Veronica Bazzani
dr Piotr Brągoszewski
mgr Żaneta Bugajska
dr Piotr Chrościcki
Aleksandra Gosk
dr Anna Kornakiewicz
mgr Łukasz Kowalski
mgr Monika Kwiatkowska
mgr Inés Juaristi Santos
mgr Tomasz Sitarz
mgr Vanessa Tolotto
dr Ulrike Topf
dr Barbara Uszczyńska-Ratajczak
dr Carlo Vascotto
Tytuł Kierownik projektu Okres Finansowanie
Wpływ inhibicji proteasomu na homeostazę mitochondrialną 2020 - 2023 OPUS 17, NCN
Wzajemna zależność pomiędzy transportem białek mitochondrialnych i komórkową homeostazą białek 2016 - 2021 MAESTRO 7, NCN
Mechanizmy odpowiedzi komórki na zaburzenia transportu białek do mitochondriów 2017 - 2020 First TEAM, FNP
Zależność między procesem translacji a dysfunkcją mitochondriów podczas stresu komórkowego 2017 - 2019 HOMING, FNP
Analiza alternatywnych szlaków importu białek do mitochondriów Aleksandra Gosk 2017 - 2019 Diamentowy Grant, MNiSW
Mitochondrial translocation of the DNA repair protein APE1 2017 - 2019 POLONEZ, NCN
Analiza translokazy białek mitochondrialnych TIM22 w komórkach ludzkich Katarzyna Chojnacka 2016 - 2019 FUGA, NCN
Charakterystyka mitochondrialnej ścieżki importu białek TIM23 w komórkach ssaków 2016 - 2019 OPUS, NCN
The link between mitochondria and the protein quality control system 2017 - 2019 POLONEZ, NCN
Principles of mitochondrial protein compartmentalization in vertebrates 2017 - 2019 POLONEZ, NCN
Cytosolic chaperone systems for mitochondrial precursor proteins. 2014 - 2018 Ideas Plus, MNiSW
Mechanisms protecting from oxidative damage during aging 2016 - 2018 OPUS, NCN
Coupling of synthesis and transport for proteins targeted to the mitochondria. 2014 - 2018 OPUS, NCN
Extramitochondrial factors regulating turnover of mitochondrial intermembrane space proteins. 2014 - 2017 SONATA6, NCN
Mitochondrial protein biogenesis in the synapse is supported by local translation
Kuzniewska B., Cysewski D., Wasilewski M., Sakowska P., Milek J., Kulinski T.M., Winiarski M., Kozielewicz P., Knapska E., Dadlez M., Chacinska A., Dziembowski A., Dziembowska M.
EMBO Rep.
Ubiquitin – proteasome system and its crosstalk with mitochondria as therapeutic targets in medicine
Kodroń A., Mussulini B.H., Pilecka I., Chacińska A.
Pharmacological Research
Mitochondrial control of cellular protein homeostasis
Mohanraj K., Nowicka U. & Chacińska A.
Biochem J (2020) 477 (16): 3033–3054
COA6 Facilitates Cytochrome c Oxidase Biogenesis as Thiol-reductase for Copper Metallochaperones in Mitochondria
Pacheu-Grau, D., Wasilewski, M., Oeljeklaus, S., Gibhardt, C. S., Aich, A., Chudenkova, M., ... & Rehling, P.
Journal of molecular biology, 432(7), 2067-2079
Mitochondrial Oxidative Stress Induces Rapid Intermembrane Space/Matrix Translocation of Apurinic/Apyrimidinic Endonuclease 1 Protein through TIM23 Complex
Barchiesi, A., Bazzani, V., Tolotto, V., Elancheliyan, P., Wasilewski, M., Chacinska, A., & Vascotto, C.
Journal of Molecular Biology, 432(24), 166713
Nutritional status and fecundity are synchronised by muscular exopheresis
Turek, M., Piechota, M., Shanmugam, N., Niklewicz, M., Kowalski, K., Chacinska, A., & Pokrzywa, W.
bioRxiv
Ovarian carcinoma immunoreactive antigen-like protein 2 (OCIAD2) is a novel metazoan specific complex III assembly factor
Chojnacka, K. J., Mohanraj, K., Callegari, S., Mussulini, B. H. M., Elanchelyan, P., Gosk, A., ... & Chacińska, A.
bioRxiv
GENCODE reference annotation for the human and mouse genomes
Frankish, A., Diekhans, M., Ferreira, A., Johnson, R., ... & Uszczynska-Ratajczak, B. (2019).
Nucleic Acids Research, 47(D1), D766-D773
Mitochondrial stress-dependent regulation of cellular protein synthesis
Topf U., Uszczynska-Ratajczak B., Chacinska A. (2019).
Journal of Cell Science, 132
Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7
Mohanraj, K., Wasilewski, M., Benincá, C., Cysewski, D., Poznanski, J., Sakowska, P., Bugajska, Z., Deckers, M., Dennerlein, S., Fernandez-Vizarra, E., Rehling, P., Dadlez, M., Zeviani, M. & Chacinska, A. (2019).
EMBO Mol Med, 11(5), pii: e9561.
A High-Resolution Luminescent Assay for Rapid and Continuous Monitoring of Protein Translocation across Biological Membranes
Pereira, G. C., Allen, W. J., Watkins, D. W., Buddrus, L., Noone, D., Liu, X., Chacińska, A., . . . Collinson, I.
Journal of Molecular Biology, 431(8), 1689-1699
Non-canonical translation initiation in yeast generates a cryptic pool of mitochondrial proteins
Monteuuis G, Miścicka A, Świrski M, Zenad L, Niemitalo O, Wrobel L, Alam J, Chacińska A, Kastaniotis AJ, Kufel J.
Nucleic Acids Res. 47(11):5777-5791
Cytosolic translational responses differ under conditions of severe short-term and long-term mitochondrial stress
Samluk L, Urbanska M, Kisielewska K, Mohanraj K, Kim MJ, Machnicka K, Liszewska E, Jaworski J, Chacinska A.
Mol.Biol. Cell 30(15):1864-1877. doi: 10.1091/mbc.E18-10-0628.
Quantitative proteomics identifies redox switches for global translation modulation by mitochondrially produced reactive oxygen species.
Topf, U., Suppanz, I., Samluk, L., Wrobel, L., Böser, A., Sakowska, P., Knapp, B., Pietrzyk, M.K., Chacinska, A. and Warscheid, B. (2018).
Nature Communications, 9(1), p.324.
Determinants of the cytosolic turnover of mitochondrial intermembrane space proteins
Kowalski L, Bragoszewski P, Khmelinskii A, Glow E, Knop M, Chacinska A. (2018).
BMC Biol. 2018 Jun 22;16(1):66. doi: 10.1186/s12915-018-0536-1.
Mitochondrial protein import stress and signaling
Samluk, L., Chroscicki, P., & Chacinska, A. (2018).
Current Opinion in Physiology
Motor recruitment to the TIM23 channel’s lateral gate restricts polypeptide release into the inner membrane
Schendzielorz, A. B., Bragoszewski, P., Naumenko, N., Gomkale, R., Schulz, C., Guiard, B., ... & Rehling, P. (2018).
Nature communications, 9(1), 4028
Loss of the Mia40a oxidoreductase leads to hepato-pancreatic insufficiency in zebrafish
Sokol, A. M., Uszczynska-Ratajczak, B., Collins, M. M., Bazala, M., Topf, U.,.... & Chacinska, A. (2018).
PLoS Genetics
LDL dinitrosyl iron complex acts as an iron donor in mouse macrophages.
Lewandowska, H., Stępkowski, T. M., Męczyńska-Wielgosz, S., Sikorska, K., Sadło, J., Dudek, J., & Kruszewski, M. (2018).
Journal of inorganic biochemistry, 188, 29-37
Towards a complete map of the human long non-coding RNA transcriptome
Uszczynska-Ratajczak, B., Lagarde, J., Frankish, A., Guigó, R., & Johnson, R.
Nature Reviews Genetics, 19(9), 535-548.
Control of mitochondrial biogenesis and function by the ubiquitin-proteasome system
Bragoszewski, P., Turek, M., & Chacinska, A. (2017)
Open biology, 7(4), 170007
Cell biology: Sort and destroy.
Chacinska, A. (2017)
Nature, 543(7645), 324-325.
Visualization of cytosolic ribosomes on the surface of mitochondria by electron cryo‐tomography.
Gold, V.A., Chroscicki, P., Bragoszewski, P. and Chacinska, A. (2017)
EMBO reports, 18(10), pp.1786-1800.

Project number: 2015/18/A/NZ1/00025

Project title: Cross-talk between the transport of mitochondrial proteins and cellular protein homeostasis

Project leader:

Agnieszka Chacinska, PhD, Professor
E: a.chacinska@cent.uw.edu.pl

Post-doctoral researchers:

Minji Kim, PhD
E: m.kim@cent.uw.edu.pl

Anna Antosiewicz, PhD
E: a.antosiewicz@cent.uw.edu.pl

PhD students:

Maria Śladowska, MSc

E: m.sladowska@cent.uw.edu.pl

Martyna Pietrzyk, MSc

E: m.pietrzyk@cent.uw.edu.pl

Source of funding: National Science Centre, Poland

Budget: 4 271 581 PLN

Project duration: 21.04.2016 – 20.04.2021

About the project:

Mitochondrion is a cellular compartment commonly known as “the power plant” of cells. To fulfill its various functions, this organelle needs more than one thousand cellular proteins. Yet, the majority of mitochondrial proteins are synthesized outside mitochondria in the cytosol and thus must be transported into mitochondria with the help of other proteins forming import machines. Dysfunctional mitochondrial protein import machines cause mitochondrial malfunctions, but also accumulation of precursor proteins in the cytosol. The Chacinska group discovered the role of the cytosolic degradation machinery in precursors’ clearance and the mechanism called the unfolded protein response activated by mistargeted proteins (UPRam) that protects the cell from stress caused by mistargeted mitochondrial precursor proteins accumulating in the cytosol. These processes pinpoint an important crosstalk between the state of mitochondria and regulatory mechanisms responsible for maintaining the cellular protein homeostasis. In the Maestro project, using simple model organisms, such as yeasts and worms, in addition to cultured mammalian cells, multidisciplinary approaches based on biochemistry, molecular cell biology and systems biology will be undertaken to identify and characterize the mechanisms of both, degradation of mistargeted mitochondrial proteins and the UPRam. We also aim to uncover biological consequences of these mechanisms, which are critical for homeostasis, survival and ageing at the cellular and organismal level.

Publications:

Sokol. A.M, Uszczynska-Ratajczak B.,Collins M.M., Bazala M., Topf U., Lundegaard, P.R., Sugunan S., Guenther S., Kuenne C., Graumann J., Chan S.S.L., Stainier D.Y.R., Chacinska A. (2018). Loss of the Mia40a oxidoreductase leads to hepato-pancreatic insufficiency in zebrafish. PLoS Genet 14(11): e1007743. https://doi.org/10.1371/journal.pgen.1007743

Samluk L., Chroscicki P., Chacinska A. (2018). Mitochondrial protein import stress and signaling. Curr. Opin. Physiol. 03, 41–48. DOI: 10.1016/j.cophys.2018.02.010

Bragoszewski, P., Turek, M., Chacinska, A. (2017). Control of mitochondrial biogenesis and function by the ubiquitin–proteasome system. Open Biol., 7 (4) 170007, DOI: 10.1098/rsob.170007.

Wasilewski M., Chojnacka K., Chacinska A.  (2017) Protein trafficking at the crossroads to mitochondria. Biochim Biophys Acta, 1864(1):125-137. https://doi.org/10.1016/j.bbamcr.2016.10.019

 

Lectures at the international conferences:

10.2018

Chacinska A.– Invited Speaker, CRC 1218 International Syposium: Mitochondrial Plasticity in Metabolism and Signalling, Max Planck Institute for Biologie of Ageing, “Guided Tour of proteins into mitochondria”, Cologne, Germany

07.2018

Chacinska A.– Invited Speaker, FASEB Conference, Protein Folding in the Cell, “Cellular protein homeostasis responses driven by mitochondria”, Buffalo, USA

Chacinska A. – Invited Speaker, The 43rd FEBS Congress, Theodor Bücher Plenary Lecture, „Mitochondria in cellular protein homeostasis”, Prague, Czech Republic

Pietrzyk M., et al. – The 43rd FEBS Congress, Poster: „Ribosome – associated quality control (RQC) in Saccharomyces cerevisiae upon oxidative stress”.

Śladowska M., et al. – Mitochondrial and Chloroplast Gordon Research Conference, Poster: „Mitochondrial protein import stress can prolong life of Caenorhabditis elegans„.

06.2018

Chacinska A. – Invited Speaker, Cell Symposia: Multifaceted Mitochondria, “The guided tour of proteins to mitochondria”, San Diego, USA

05.2018

Chacinska A. – Invited Speaker, EMBO Workshop: Molecular Biology of Mitochondria, “Mitochondria and cellular protein homeostasis mechanisms”, Stockholm, Sweden

09.2017

Chacinska A. – Invited Speaker, FEBS Congress: Protein Trafficking at the Crossroads to Mitochondria, Jerusalem, Israel

07.2017

Chacinska A. – Invited Speaker, EMBO Workshop: Mitochondrial quality control, “UPS-dependent degradation of mitochondrial precursor”, Xi’an, China

11.2016

Chacinska A. – Invited Speaker, International Conference of the Centre for Misfolding
Diseases 2016, “Protein homeostasis at the crossroads to mitochondria”,
Sevilla, Spain

11.2016

Chacinska A.Invited Speaker, Protein Biogenesis & Mitochondrial Dynamics, “Protein
trafficking at the crossroads to mitochondria”, Baiersbronn-Obertal, Germany

09.2016

Turek M., et al. – The 2nd Congress BIO 2016: “Expanding beyond the limits”, Wroclaw, Poland

Posters at the international conferences:

09.2016

Śladowska M., Topf U., Chacinska A., Poster Session at the 7th EMBO meeting, “Effects of mitochondrial dysfunction in Caenorhabditis elegans”, Mannheim, Germany

The „Regenerative Mechanisms for Health” International Research Agenda Unit (“ReMedy”) is a joint unit of the University of Warsaw and University Medical Center Göttingen at Georg-August-University Göttingen, funded by a grant by the Foundation for Polish Science. The goal of ReMedy is to understand and to harness stress‐evoked adaptability of cells at the molecular and biochemical level, in order to combat human diseases and pathologies.
Director: prof. Agnieszka Chacińska 
Deputy director: prof. Magda Konarska
Project coordinator: dr Michał Wrzesiński
Administration Manager: mgr Marzena Niedźwiadek 
Project and Lab Managers: dr Agnieszka Gajewska, dr Iwona Pilecka
Financial Administrative Specialist: mgr Sebastian Pomirski – Ciura
ReMedy aims to:

  • understand mechanisms of stress response
  • discover short- and long‐term consequences of cellular responses and their crosstalk in physiology
  • apply the gained knowledge about stress responses for the development of new medical treatments.
Prof. Chacińska will seek to identify global consequences of translational inhibition in human cells. Preliminary data show that although acute stress leads to rapid inhibition of protein synthesis, this stress is not lethal and frequently cells become even more resistant to further insults. Unknown adaptive mechanisms lead to re-initiation of protein translation. Prof. Chacińska’s group will undertake a system analysis of gene expression changes that accompany dysfunctional mitochondria, aiming to identify changes in transcription various steps of mRNA biogenesis and stability, including splicing – in collaboration with the Konarska lab – as well as translation activity/recruitment of mRNA during translation initiation. Studies of the group will deliver a comprehensive gene expression profiling under mitochondrial dysfunction and will lead to a discovery of yet unknown responses and adaptive pathways that have a potential to rescue cells and organisms from organellar stress and may in general benefit cellular and organismal fitness.

Prof. Konarska group will study the mechanisms by which aging or environmental signals influence the function of the splicing machinery and affect splicing outcomes. Changes in patterns of alternative splicing in higher eukaryotes are characteristic signatures of stress and disease, but little is known about the underlying mechanisms. These studies will help to understand how environmental changes or ageing affect regulation of gene expression at the splicing level. They will also help to understand the function of the spliceosome and suggest new ways to modulate it. Ultimately, the mechanisms utilized by yeast to regulate pre-mRNA splicing will also be validated in mammalian cells, and the way how they affect more complex regulation of alternative splicing will be studied in collaboration with the Chacińska group.

 

ReMedy is funded by Foundation for Polish Science International Research Agendas Programme (project MAB/2017/2) under measure 4.3 „International Research Agendas“, Smart Growth Operational Programme 2014-2020.

 

 

mgr Michał Bazała
mgr Veronica Bazzani
mgr Anita Brewińska
mgr Magdalena Chojnacka
dr Piotr Chrościcki
mgr Tomasz Czerwik
mgr Magdalena Długołęcka
mgr Jakub Dominowski
dr Beata Drabarek
mgr Aleksandra Fergin
mgr Edyta Głów
dr Agnieszka Górnicka
dr Elżbieta Januszewicz
mgr Inés Juaristi Santos
dr Magdalena Kaus-Drobek
dr Adrianna Łoniewska-Lwowska
mgr Aleksandra Matusiak
mgr Inmaculada Mora Espi
mgr Kamila Ornoch
mgr Sabine Poerschke
dr Paulina Sakowska
dr Anna Sokół
dr Małgorzata Sztolsztener
mgr Krzysztof Tarasiuk
mgr Vanessa Tolotto
mgr Agata Trojanowska
dr Aksana Varabyova
dr Lidia Wróbel