Tricks of the trade

By | Science & Technology
Mitochondrion structure. Credit@Kelvinsong

For the first time, scientists have demonstrated the shuttling of DNA between mitochondria – a previously unobserved phenomenon. The findings are published in biological journal Cell Metabolism. The study reveals how DNA from the mitochondria of mice may be transferred from healthy tissues into tumour cells to promote cancer growth.

Most cells contain between several hundred to tens of thousands of mitochondria; 30-40% of hard muscle cell mass is made up by mitochondria. Their shapes may be very varied, even within the same cell type, especially when exposed to different conditions. Typically they have a diameter of approximately one micrometre and are shaped like elongated balloons, although many other shapes have also been found, such as reticulate networks. The diagram below shows how mitochondria have two membranes – an outer and an inner – that surrounds the matrix. The matrix is packed with metabolic enzymes, such as those required to convert food into energy that the cell might use. This matrix also contains 2-10 copies of small, circular mitochondrial DNA (mtDNA), with a complete system for replication including DNA and protein synthesis.

Mitochondrial DNA comprises a very small proportion of the total DNA in most cells, containing only 37 genes compared to more than 20,000 in nuclear DNA. Yet, this “second genome” was the first part of the human genome to be sequenced. Mitochondrial DNA is also more prone to error and therefore accumulates DNA damage more quickly than nuclear DNA. This is because fewer proteins, for example histones, are associated to it, leaving it exposed to the surrounding microenvironment. Nevertheless, it contains genomic information for one of the most important processes in the human body – energy production – which indicates how the transfer of this DNA might strengthen tumour cells and help them spread.

The team, led by Professor Mike Berridge from the Malaghan Institute of Medical Research in New Zealand and Professor Jiri Neuzil from the Griffith University in Australia, were investigating potential cancer treatments by assessing whether removing mtDNA from cancer cells might inhibit their development into tumours. To achieve this, the researchers generated breast tumour cell lines deficient in mtDNA, representative of extreme mitochondrial damage. Initially, they observed slowed growth in the tumour cells in mice. To their surprise however, a few months later, they noticed tumours appearing.

Thinking that tumour cells without mitochondrial DNA were unlikely to grow, Professor Berridge explained in a news release that, “A normal person would have terminated the experiment after a week, before this effect was observed…(we) kept monitoring them for more than a month and eventually saw tumours starting to grow.”

The next challenge was then to find out how these cells managed to grow in the absence of mtDNA. Using the latest genetic sequencing technology, the team eventually found that the cells contained mtDNA that had been transferred from healthy, non-tumour cells. This allowed the tumour cells to regain their respiratory ability and produce the energy required for growth. Scientists are eager to establish if this phenomenon is an important part of tumour formation. Preliminary studies are suggesting that this may already be a common process in the brain and that mitochondrial gene transfer between cells might be a common event overlooked by the reduced sensitivity of traditional techniques.

Dark field image (left) highlights the transfer of fluorescent mitochondria to breast cancer cells lacking mitochondrial DNA. Bright field (right) has sufficient light to see the connecting nanotube. Credit@MalaghanInstitute.

Dark field image (left) highlights the transfer of fluorescent mitochondria to breast cancer cells lacking mitochondrial DNA. Bright field (right) has sufficient light to see the connecting nanotube. Credit@MalaghanInstitute.

Fundamentally, the study demonstrates how large mitochondrial deletions may be repaired by the acquisition of host mtDNA, although its mechanism remains unclear. Additionally, it showcases the tumour cell’s extraordinary ability to overcome particularly withering conditions in and around the cell. The team is looking to follow up this work by investigating the minimum level of damage required to initiate mtDNA transfer as well as explore where else this process might be observed in the body. Research into this mechanism might also guide medical genetics into replacing or repairing unhealthy genes with synthetic DNA.

What other discoveries have similarly surprised scientists, changing the way they view the world?


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