21 May 2015

DNA Trafficking Between Cells

From Our Changing World, 9:34 pm on 21 May 2015

We have been doing work with two different brain cell types, astrocytes and neurons, and have been able to show that in early development … mitochondria can track between cells. This seems to be a normal communication process between cells.
Mike Berridge, Malaghan Institute

James Baty, left, and Mike Berridge

James Baty, left, and Mike Berridge, are part of the Malaghan Institute's team that discovered mtDNA transfer between cells in animals. Photo: Malaghan Institute of Medical Research

In a world first, scientists have found that DNA can shuttle between cells in an animal.

The discovery describes a fundamentally new process that challenges textbook science and will undoubtedly open up new areas of research – but perhaps more importantly, it raises the possibility of new therapies for diseases of the heart and brain, including neuro-degenerative conditions such as Alzheimer's and Parkinson's, and possibly cancer.

Lead by cell biologist Mike Berridge at the Malaghan Institute of Medical Research in Wellington and Jiri Neuzil at Griffith University in Queensland, Australia, the team found that tumour cells that had their mitochondrial DNA removed can import replacement DNA from surrounding, healthy cells.

Cellular power generators

Most of our DNA is bundled up tightly in chromosomes in the nucleus of each cell, but there is also a much smaller amount of DNA inside cellular structures called mitochondria. These organelles act as power generators, producing the energy a cell needs for chemical reactions. This mitochondrial DNA, or mtDNA, codes for only 37 genes (as opposed to around 20,000 genes inscribed in our nuclear DNA) and is sometimes referred to as the second genome.

Mike Berridge has a long-standing interest in how cells produce their energy – driven by the fact that mitochondria are clearly the main source in healthy cells, but cancer cells rely on a different mechanism.

A key question for his team is whether removing mtDNA from cancerous cells could thwart the development of tumours. To answer that question, they developed a melanoma and breast cancer cell line with no mitochondrial DNA, which grew well in cell culture, and injected these cells into a mouse.

Mike Berridge says that if these cancer cells have functioning mtDNA, they invariably grow into aggressive tumours that metastasise and spread throughout the body within seven days.

“We were able to show that these cells without mitochondrial DNA would not grow as a tumour for quite a while, for a month. They just sat there, but then all of a sudden they started to grow, and they grew almost up to the rates of normal tumour cells.”

The team checked the tumour cells and found that they had somehow acquired mtDNA, and after more detailed tests it was clear that the DNA they now carried had come from the healthy cells surrounding the tumour.

These images show the transfer of mitochondria, via a nanotube, between breast cancer cells in a mouse.

These images show the transfer of mitochondria, via a nanotube, between breast cancer cells in a mouse. This is the first time mitochondrial DNA transfer has been observed in an animal tumour. Photo: Malaghan Institute of Medical Research

“We found differences that showed that the mitochondrial DNA was the genotype of the mouse into which the cells had been injected,” he says.

Showing that this transfer of mtDNA was happening was one thing. The next challenge was to work out how, and it turns out that it might not be just the mtDNA that shuttles between cells, but the whole mitochondrium. And what’s more, this could be a common repair and maintenance mechanism in the body.

There’s evidence that stem cells can supply mitochondria to heart muscle cells that have damaged mitochondrial DNA. That opens up an area of whether or not hearth problems that relate to energy supply in cardiac muscle, or in fact any muscle system in the body, might invoke the mechanisms of mitochondrial transfer to repair damaged systems.

The Malaghan Institute team is even more excited about the prospect that mitochondrial transfer could play a major role in healthy brain function as well as in neuro-degenerative conditions such as Alzheimer's and Parkinson's.

“We have been doing work with two different brain cell types, astrocytes and neurons, and have been able to show that in early development, or in neonatal cultures, mitochondria can track between cells. They move along connections between cells and the astrocytes will supply the neurons with mitochondria. Now this is in situations were we’re not damaging anything. This seems to be a normal communication process between cells.

“We’re very excited about this because this might bring in a new idea that brain cell function is contributed to by mitochondrial replacement from cells that maintain the nerve cells but are not nerve cells themselves.”

Given the brain’s high need for energy, this discovery could mean a rethinking of healthy brain development.

Nerve cells in our bodies can extend from the bottom of our spine down to our big toe, half a metre or a metre. In whales one nerve cell can extend 30 metres, and then you have the dilemma of how all the energy required at the nerve ending is provided and maintained throughout the life of that neuron, which may be years.

The textbook version is that mitochondria travel along the length of the neuron, but Mike Berridge says his team’s work suggests that “this might be going on at a local level, by DNA transfer between different cell types to maintain that high energy demand of nervous cell function and brain function”.

He says that the process might even work both ways. “There’s preliminary evidence that suggests that optic nerve cells can package up damaged mitochondria and transfer them to another cell type, the astrocyte, for processing. So our idea would be that the process can occur in reverse, that astrocytes can provide healthy, young, vibrant mitochondria to maintain nerve function throughout the life of that neuron.”

The findings also raise the possibility of new therapeutic approaches to neuro-degenerative diseases such as Alzheimer's and Parkinson's.

“Do [these conditions] really have a component of a restriction of the energy supply system in the brain? If they do, can we get in there and do something about it. Can we understand the processes that go on in the brain that control that energy.”

Apart from healthy brain and heart function, mitochondria are also associated with more than 200 diseases, which involve changes in mtDNA. Mike Berridge says that understanding the processes whereby mitochondria can move between cells could help to improve the body’s repair mechanisms and to address problems relating to mitochondrial diseases.

As far as new cancer therapies are concerned, he is cautious. “Mitochondrial function is needed by tumour cells, but tumour cells don’t use their mitochondria a lot. The more mitochondrial activity, the more a cell is driven to differentiate and to function, so it won’t divide very well if it’s using its mitochondria all the time. There might be a way of manipulating the balance to drive cells to use their mitochondria and essentially differentiate.

We think that cancer cells need an optimum amount of energy. If they have too much from their mitochondria, they won’t continue as cancer cells. If they have too little or none, they can’t grow as cancers, so understanding what the tumour cell needs and how to push it outside of its comfort zone may be very important in addressing tumours. It’s about understanding the biology behind the processes … which might then lead us on to be able to control that process, and to control cancer in that away.