Secret agent protein could help understand longevity and cancer

The double life of a tiny protein might have big implications for research in longevity, cancer, neurodegenerative and inflammatory diseases.

A team of German and Australian scientists has found that the protein “TFEB” plays a big role in helping mitochondria – the so-called “powerhouse of the cell” – to function.

Transcription factor EB, or TFEB, was known to be a protein that helped with transcribing DNA in the nucleus of a cell. It also helped with autophagy: recycling and clearing out junk in the cell.

“It’s not only present in humans – it’s also present in other species of animals, but in very small animals like worms it’s not present in mitochondria,” says Dr Nirmal Robinson, a senior research fellow at the University of South Australia’s Centre for Cancer Biology, and senior author on a paper published in EMBO Reports.

More recently, researchers had started to understand that TFEB is also involved in regulating mitochondria.

Mitochondria convert energy into the highly transportable molecule ATP, as well as helping metabolise things and provoking inflammation when there’s an external threat.

“TFEB played a major role in longevity – that’s how we got interested in it,” says Robinson.

But once they’d started investigating it, Robinson and his colleagues at the University of Cologne and the Max Planck Institute, both in Germany, found that TFEB was working in mysterious ways.

“The striking thing that we found was even if it does not move into the nucleus, if you deplete the protein, then there was an increase in inflammation.

“So that said that it should have some function other than just in the nucleus.”

Through a series of different tests – including testing the reaction of TFEB to invasive bacteria, assays to see which proteins TFEB sticks to, then electron microscopy – the researchers uncovered a more detailed picture of what the protein was up to.

They found TFEB wasn’t just sticking to the outside of the mitochondria – it was moving right into the inner regions. And weirdly, even though there’s DNA inside the mitochondria too, the protein wasn’t working with DNA.

“It binds to a protein called LONP1, which is a mitochondrial protease,” says Robinson.

Together, TFEB and LONP1 work with a thing called the mitochondrial complex I, which helps regulate the energy moving through the mitochondria. Robinson says it “applies a brake” to mitochondrial function, stopping it from becoming too reactive and increasing inflammation.

“It’s very unconventional, and it has not been shown before,” says Robinson.

“There are many proteins which have been shown to do multiple things. But not many transcription factors like TFEB, which move into the nucleus, could also move in inside the mitochondria – because the proteins which move into the mitochondria are very strictly regulated.”

TFEB’s mitochondrial multitasking has wide-ranging implications for disease research.

“One of the things that we see is that when you don’t have this protein moving into the into the mitochondria, some cancer cells tend to multiply very rapidly. That suggests that the mitochondria cannot be just revving itself uncontrollably. You need this [protein] to go and put a brake on it,” says Robinson.

It could also play a role in aging-related diseases, and inflammation. Robinson and colleagues are hoping to run studies on mice and other animals, like fish, to see what happens if this protein is left in the nucleus, but doesn’t make it across to the mitochondria.

“What happens to an animal when that protein is not able to move into the mitochondria? Will they age normally? Will there be a problem in aging and in cancer models? What does it do in terms of disease pathologies?” asks Robinson.

Such research would lead to developing new therapeutics, although on-the-shelf medicines are likely decades away.

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