Current Projects

Structural Basis of RNA Delivery to Mitochondria for Gene Therapy

Principal Investigator: Katarzyna Bandyra (Project partners: Ben Luisi and ExploRNA Therapeutics).

Mitochondria are essential organelles that serve as central regulators of metabolism and various critical processes, including apoptosis. Since they have their own genome, mutations within mitochondrial DNA can lead to severe diseases. Despite significant advancements in gene therapy, we currently lack effective methods to deliver nucleic acids directly to the mitochondria, limiting our ability to treat these disorders. This project aims to investigate potential RNA transport mechanisms into human mitochondria and leverage these pathways to design synthetic RNA molecules – MitoGuides – capable of mitochondrial uptake. By understanding these mechanisms, we seek to establish the foundation for mitochondrial gene therapy, paving the way for novel treatments for mitochondrial diseases.

Funding source:

FIRST TEAM FENG, Foundation for Polish Science

SEE project page (EN)

Post-transcriptional regulators from the Fas-activated serine/threonine kinase protein family

Principal Investigators: Katarzyna Bandyra, Maria Górna, Daria Dawidziak

We are very interested in mitochondrial proteins, since the mitochondrion is an essential organelle as the main source of ATP and which has fundamental roles in all aspects of cell biology, ranging from cell death to growth, differentiation and inflammation. Unsurprisingly, mitochondrial malfunction is associated with a plethora of diseases including cancer, diabetes, neurodegenerative diseases and inflammatory disorders. Proteins which are involved in pathological processes constitute therapy targets and their structures may be used in drug design. In addition, mitochondrion is an intriguing study subject due to its origin in endosymbiosis of a prokaryotic ancestor. Mitochondrial proteins often combine elements of the prokaryotic and eukaryotic worlds or offer an opportunity to discover new protein architectures. One such intriguing group of proteins is the Fas-activated serine/threonine kinase (FASTK) family which participates in the regulation of mitochondrial RNA metabolism. Excitingly, FASTK family members contain putative novel RNA-binding domains of unknown structure, including a potentially new type of helical repeats.

In another extension of this project, we also study non-mitochondrial roles of FASTK in alternative splicing and stress response. Due to its involvement in the alternative splicing of Fas mRNA, FASTK is also a putative target for anti-inflammatory therapeuticals. Once the structure of FASTK becomes available, it may enable us to design drugs against this protein which could help treat autoimmune diseases such as asthma or rheumathoid arthritis.

Our latest interest in this area is investigation of structures and interactions of FASTKD1-5 - by the newly expanded team of dr Bandyra.

Funding sources:

SONATA BIS 13, SONATA 8, PRELUDIUM 19, National Science Centre, Poland;

the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 655075

Structural and functional studies of human PNPase in mitochondrial RNA metabolism

Principal Investigator: Katarzyna Bandyra

Human polynucleotide phosphorylase (hPNPase) is a highly conserved exoribonuclease residing mostly in the mitochondrial intermembrane space, where its function is poorly understood. In bacteria, where the enzyme is best understood, PNPase can be re-programmed by the RNA chaperone Hfq and small regulatory RNA (sRNA) to switch from degradative to chaperoning roles in RNA-mediated gene regulation. As the human and bacterial enzymes are homologues, it is possible that hPNPase could have a dual mode of action as well, and could participate in diverse RNA-mediated regulatory processes once trapped in a non-degradative assembly. Our research will address what functions are played by hPNPase present in the intermembrane space of the human mitochondria. We will characterise the full-length enzyme and its capacity to bind substrates in the degradative and non-degradative modes, as well as identify potential hPNPase ternary complexes. In order to achieve these objectives, we will elucidate the structure-function relationship of hPNPase by cryo-EM.

Funding sources:

POLS, National Science Centre, Poland & EEA and Norway Grants - SEE PROJECT PAGE (EN) | STRONA PROJEKTU (PL)

Sonata 16, National Science Centre, Poland

the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 101038064 (WIDENING FELLOWSHIP)

EMBO Installation Grant #5035

Page updated

Report abuse