Project information
Mitochondrial Transfer Coding via Nucleic Acid Structure and Recognition (MITOCODE)

Mitochondria are essential for cellular homeostasis, metabolism, and stress adaptation, and their intercellular transfer has emerged as a critical process in tissue regeneration, immune responses, and tumour progression. Cancer cells, in particular, can hijack mitochondria from stromal or immune cells, thereby boosting ATP production, buffering oxidative stress, and gaining therapy resistance. While physical transfer routes such as tunnelling nanotubes and extracellular vesicles (EVs) are increasingly well characterised, the molecular signals that trigger and regulate this communication remain elusive.
MITOCODE proposes that noncanonical RNA structures, G-quadruplexes (rG4s), act as signals that couple mitochondrial RNA fate to organelle export. To probe this mechanism, MITOCODE leverages in-organelle solid-state NMR, in-cell solution NMR, and engineered inducible monoclonal cell lines with molecular biology and cell imaging.
Two aims guide MITOCODE:
(1) Mitochondrial selection: defining how GRSF1, a mitochondrial protein that remodels mitochondrial RNA, controls the folding state of mitochondrial rG4s and thereby their retention or release from mitochondria.
(2) EV loading: uncovering how YBX1, an oncoprotein that facilitates loading of G-rich RNAs into extracellular vesicles, recognises rG4s and promotes their sorting into extracellular vesicles under stress.
Together, these aims will determine how RNA secondary structure encodes an export code for mitochondrial communication. MITOCODE will provide the first structural framework for mitochondrial RNA export and pioneer a platform to study RNA–protein interactions directly within organelles using solid-state NMR. MITOCODE thus combines conceptual and methodological innovation: it positions RNA structure as a determinant of intercellular communication and delivers a broadly applicable NMR-based framework. Ultimately, these advances will open new perspectives on cancer biology and therapy resistance.