Transport of RNA Across Mitochondrial Membranes: towards mitochondrial genome editing
(TRAMM)
Recent developments in DNA editing technology, including the CRISPR/Cas9 system, marked a revolution in the way we approach biological research and represent a giant leap forward in our ability to understand and treat diseases by eliminating their root cause.
In spite of this enormous potential, a relatively small but crucially important fraction of the DNA that regulate our cells still remains beyond our reach. This “untouchable” DNA is contained in very special organelles of the cell, called mitochondria. Mitochondria are often called the “powerhouse” of the cell, because they provide the bulk of energy needed especially in cells such as muscles and brain cells. It is therefore not surprising that mutations in the mitochondrial DNA can lead to devastating and largely intractable diseases that affect primarily brain and heart, along with several types of cancer.
The reason why the mitochondrial DNA is so difficult to edit resides the peculiar structure of the mitochondria themselves: the mitochondrial DNA is separated from the cytoplasm of the cell by two membranes. These membranes are highly impermeable to nucleic acids, which represent a crucial component of genome-editing technologies.
Currently there is no reliable way to transport nucleic acids across mitochondrial membranes. However, this may be about to change thanks to the flurry of research that has been spurred by the COVID-19 pandemic. It has been recently discovered that coronaviruses have the ability to synthesize a set of proteins that collectively build a channel. And this is no ordinary channel: it is the only know example of a channel sitting on two membranes, and able to transport RNA across them.
The aim of this project is to reconstitute and study this protein channel, finding out how it works and how we can re-purpose it to transport RNA in mitochondria. If this strategy works, we will be finally able to edit the mitochondrial DNA, in the same way we edit the nuclear DNA. This could allow to study a number of devastating diseases that originate from mutations in the mitochondrial DNA, and for which there are currently very limited treatments available.
Principal Investigator:
Dr. Nicola De Franceschi (n.defranceschi[at]imol.institute)
Project location:
Membrane Machines Laboratory
IMol PAS
ul. M. Flisa 6, 02-247 Warszawa (Poland)
De Franceschi's group website at IMol:
https://www.imol.institute/nicola-de-franceschi
Short description of the lab:
Membranes are one of the fundamental biological polymers and they underpin a myriad of functions in the cell. But membranes are also intriguing with respect to their unique biophysical properties. This 5 nm-thick, fluid material is able to bridge scales across biology, holding an entire cell together while integrating the function of individual proteins that work at the nanometer scale. Membranes can expand and re-shape, undergo fusion and fission events, and even self-repair. And they do all of this with grace and elegance, enchanting us with their stunning beauty.
We use a bottom-up reconstitution approach to study biological nanomachines that function on membranes, such as membrane pores and membrane-deforming proteins.
However, we are not limited to naturally occurring proteins: we also use other biopolymers such as nucleic acids to build bio-inspired machines that act in concert with membranes to create new functionalities.
Finally, we are interested in studying the still underappreciated role of membranes in the origin of life.
This research is port of the project No. 2022/45/P/NZ1/01565 co-funded by the Notional Science Centre and the European Union Framework Programme for Research and Innovation Horizon 2020 under the Morie Sklodowsko-Curie grant agreement no. 945339.