Mitochondria gene trade

The secret behind cancer's resilience?
07 October 2022

Interview with 

Patrick Chinnery, University of Cambridge




Cambridge scientists have discovered something surprising is going on in our cells that we’d overlooked for years. Structures called mitochondria - which used to be bacteria before they merged with our ancestors’ cells billions of years ago in a partnership that now supplies us with the energy that keeps us alive - contain their own bacteria-like DNA, separate from our main cellular genome. But Patrick Chinnery has discovered that pieces of mitochondrial genetic code periodically cut and paste themselves into our chromosomes; and this is especially true in cancers, which might explain some of the growth and resilience characteristics that cancers display.

Patrick - We got the first clue a few years ago when a group in the United States reported the transmission of mitochondrial DNA from fathers to children. This was a crazy suggestion to the field. So we went looking for an alternative explanation, and what we found was that it wasn't the mitochondrial DNA that was coming from the father, it was the nuclear dna. But what had happened is bits of the mitochondrial DNA had gone into the father's nuclear dna.

Chris - We should clarify the mitochondria, which are these cell powerhouses are in the cell, therefore they're in the egg cell that gives rise to an individual. They're not in the sperm. They're not transmitted from the sperm, which is why you're saying there's that distinction. You get your mitochondria from your mum, not from your dad.

Patrick - From our mum. They thought it was coming from the dad. We've shown it's not the case.

Chris - How did you prove that that was what was going on?

Patrick - So we worked with colleagues at Genomics England who've been carrying out the hundred thousand genomes project. People across the whole of the NHS have been contributing samples to this, and we looked at the genomic sequence of over 60,000 individuals and 12,000 cancers and looked for the signature of these bits of mitochondrial DNA across all of these individuals.

Chris - How is it getting from the mitochondria, which has got its own little circle of DNA inside these structures inside our cells, and it's getting from a totally different part of the cell into the nucleus, the headquarters of the cell, and into a chromosome in there. How is that happening?

Patrick - It's a very good question and we don't know the answer to. We're embarking on a programme to work that out. We think what's happening is that as the mitochondria recycle, bits leak out and cross into the nucleus through holes in the membrane that surround the nucleus itself and integrates them into the chromosomes, which is how the nuclear genomes packaged.

Chris - The mitochondrial DNA has got instructions in it that keep those cellular powerhouses happy. It it's how they operate. What's the consequence of pasting bits of those genetic instructions into the main chromosomes in our cell? Is there one?

Patrick - It all goes back to how mitochondria originated and the idea was when they first came into the cell, they passed on certain functions to the cell. To do that they passed DNA. So actually what we're seeing now is a consequence of that process. All of this was thought to happen billions of years ago, but actually we've measured it happening in families and, in one in 4,000 families, a new bit of mitochondrial DNA goes into the child. It's never been seen before at that rate. And in cancers it's even faster.

Chris - What about the reverse direction?

Patrick - It doesn't happen, and there are several reasons why that might be the case. One is that you've got many, many more copies of mitochondrial DNA in Excel than the nucleus. The other is that there are holes in the nucleus that allow mitochondrial DNA to go in, but not the other way around.

Chris - Right. Okay. So it is a one way street and the consequences of this stuff going in, you mentioned cancer, and it does appear to occur more frequently in cancer cells when you look. Now, is that just a hallmark of the fact that cancer is a genetic disease and therefore a genetically unstable cell? It's more susceptible to this happening or is there more to it than that?

Patrick - We've looked at where these stick in the nuclear genome and looked at the pattern of that. And what we found is that they sit nearby breaks in the genetic code. So anything that causes your genetic code to break up will attract these, bits of mitochondrial DNA that effectively behave like bandaids in the short term to repair the genetic code. So in cancer you get a very unstable nuclear genetic code and one consequence of that is the mitochondrial DNA can find its way in there.

Chris - Could it endow the cell that's cancerous with enhanced properties to be even nastier?

Patrick - It could, and we found rare examples where, in actual fact, the inserted mitochondrial DNA probably caused a cancer by disrupting a gene that's protective against cancer.

Chris - The reason for asking that, I spoke to someone recently who published a paper in the journal eLife where they said, 'well, when you look at a cancer, it's under enormous pressure. The cells are being squeezed and squashed all the time. And if you look at the effect of being squeezed and squashed on the cells, it seems to make them tougher.' And they've built experiments where they're saying, 'what doesn't kill you makes you stronger.' And it's quite literally the case with these cancers. If they squeeze the cells, they get nastier. They're more resilient, they're more robust, they're more likely to spread around the body. They also said they're more likely to have the nuclear membrane that holds all the chromosomes in break apart temporarily under those circumstances. So do you think then, I'm just speculating here, what they're seeing is a product of being likely to spew out bits of genetic material all over the place and make the process you've seen happen.

Patrick - Could well be. We don't know whether or not this is hitchhiking on the back of something that happened before the cancer formed or whether the actual cancer mechanism is leading it to happen more often.

Chris - And just briefly then, Patrick, can we turn the tables on this and if we know this is happening, we know that these things are a bandaid for cancer cells, can we unstick that bandaid and use it as an Achilles heel for cancer?

Patrick - Good question. That's for future research, Chris.

Chris - So you don't know. Interesting, though, he didn't answer the question, which means you probably already have a research project I'd say on that. Is that true?

Patrick - Possibly <laugh>.


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