A team led by Professor Mike Berridge from the Malaghan Institute has become the first in the world to demonstrate mitochondrial DNA movement between cells in an animal tumour. Their paper was published today in the leading biological journal Cell Metabolism.
The research lays important groundwork for understanding human diseases other than cancer, since defective mitochondrial DNA is known to account for around 200 diseases and is implicated in many more. It could also usher in a new field where synthetic mitochondrial DNA is custom-designed to replace defective genes.
In mouse models of breast cancer and melanoma that had had their mitochondrial DNA removed, replacement DNA was acquired from surrounding normal mouse tissue. After adopting this new DNA, the cancer cells went on to form tumours that spread to other parts of the body.
Professor Berridge says the landmark discovery could open up whole new areas of research.
“Our findings overturn the dogma that genes of higher organisms are usually constrained within cells except during reproduction. It may be that mitochondrial gene transfer between different cells is actually quite a common biological occurrence.”
Although other research groups have seen mitochondrial DNA move between cells in the laboratory, the Malaghan team is the first to demonstrate the transfer in an animal tumour model.
Professor Berridge says the research wouldn’t have happened without the extraordinary patience of his research colleague, An Tan.
“A normal person would have terminated the experiment after a week, before this effect was observed, thinking that the tumour cells without mitochondrial DNA weren’t going to grow. But Tan kept monitoring them for more than a month and eventually saw tumours starting to grow.”
The next challenge for the team was to find out how this was possible.
“Initially we thought the cells had learned to grow without needing mitochondrial DNA. But when we presented the research at a conference, a well-known scientist asked if we had tested the growing cells to see if they contained mitochondrial DNA. We hadn’t.”
A simple experiment confirmed the presence of mitochondrial DNA and extensive molecular, biochemical and protein analysis with international collaborators established that the mitochondrial DNA had, in fact, been obtained from non-tumour cells. The latest genetic sequencing technologies were used to confirm that the adopted mitochondrial DNA was distinct from that of the original tumour, but identical to surrounding non-tumour cells.
“This appears to be a basic physiological mechanism in the body that no one has seen before because they lacked the exploratory tools. Whether this new phenomenon is important in tumour formation is still unclear, but we are interested in pursuing the research to see if the transfer occurs more widely in the body. Preliminary evidence indicates it may be a common occurrence in the brain.”
Many copies of mitochondrial DNA, a small circular bacterial-like genome, are found inside each mitochondria. This DNA encodes key proteins in the mitochondrial machinery that converts energy from food into a form of chemical energy that is particularly important for brain and muscle function.
Mitochondrial DNA is unrelated to nuclear DNA, which encodes a person’s primary genetic instructions, including characteristics such as hair colour, height and sex. Mitochondrial DNA is inherited solely from a person’s mother – a trait that has been used to trace all living humans back to a common ancestor who lived in Africa 60 –70,000 years ago.
Tan, An S. et al. Mitochondrial Genome Acquisition Restores Respiratory Function and Tumorigenic Potential of Cancer Cells without Mitochondrial DNA. Cell Metabolism , Volume 21 , Issue 1 , 81 – 94. DOI: 10.1016/j.cmet.2014.12.003