Mitochondria are the powerplants of the cell, more or less. There is a herd of mitochondria in every cell, dividing like bacteria as necessary to keep up their own numbers. Their most important - but by no means only - activity is the generation of adenosine triphosphate (ATP) molecules used as chemical energy stores to power cellular processes. Mitochondria have their own DNA separate from that in the cell nucleus, and it encodes a few vital pieces of protein machinery used in the process of generating ATP. Unfortunately this DNA often becomes damaged in ways that evade cellular quality control mechanisms and lead to a takeover of the cell by malfunctioning mitochondria. The details of this takeover are still under investigation: researchers never see it happening, only the before and after state, which suggests that it is fairly rapid at least. Cells in this dysfunctional state are thought to contribute to a range of age-related conditions by exporting a flood of reactive molecules and damaged proteins into surrounding tissues.
One of the challenges in studying the progression of mitochondrial damage is that mitochondrial dynamics are highly complex. Mitochondria are like bacteria in that they multiply by division, copying their DNA and assembling new ATP-creation machinery in the process. Equally they are also like other cell components in that various complicated processes monitor them and destroy them when they show signs of wear. Further, they can also fuse together, and any two individual mitochondria can contain more than one copy of the mitochondrial genome and differing amounts of molecular machinery. To make matters even more entertaining individual mitochondria promiscuously swap components of that molecular machinery between one another. So you can probably see that it is not exactly straightforward to track the process by which a few thousand of these entities in one cell move rapidly from a state in which one mitochondrion has damaged DNA to that same DNA damage being present in all of the mitochondria. There are dozens of distinct mechanisms at work, few of which are fully understood at this time, and all of which have their own particular constraints and reactions to circumstances.
As is the case for many areas in aging, however, researchers could skip over all of this complexity and bypass full understanding in order to sprint down a more direct path towards treatments. The SENS approach to work on rejuvenation treatments, for example, picks out provision of proteins encoded in mitochondrial DNA as the key point. Provided that those proteins are supplied, it doesn't matter what happens to the mitochondrial DNA, as the necessary machinery is still there. The mitochondria will continue to function correctly rather than malfunction. On that basis there are a number of ways to go: deliver replacement mitochondrial genomes while clearing out existing genomes, put copies of mitochondrial genes into the cell nucleus (plus solve the thorny problem of how to transport the proteins produced back into the mitochondria), deliver RNA that will manufacture proteins at the mitochondria, and so forth. None of these methods requires a full understanding of how mitochondrial damage progresses in order to be effective, but as is usually the case in these matters none of them are well funded in comparison to efforts to generate the full understanding of mitochondrial dynamics. Science as practiced is very much biased towards the generation of understanding first and foremost, which sometimes leaves practical paths towards treatments lost and languishing.
In any case, back to the complexity of mitochondrial dynamics: there is yet another level to all of this that has come under investigation in recent years, which is that cells can under some circumstances exchange components such as mitochondria. Stem cells have been shown to donate mitochondria to other cells in tissues where they are needed due to dysfunction, for example. Here researchers investigate another case in which this happens, making use of some of the more recent advances in the tools of biotechnology:
Researchers discovered that when mitochondrial DNA was removed from mouse models of breast cancer and melanoma, after about a month or so, this DNA was naturally replaced by the surrounding healthy tissue. This allowed the cancer to form tumours and continue spreading around the body, because mitochondrial DNA is responsible for encoding key proteins that are used in the process of converting the energy from our food into the chemical energy that we use to fuel our brain and muscle function.
"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. 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."
Defective mitochondrial DNA is known to cause around 200 diseases, characterised by the way they affect a person's hearing, eyesight, brain and muscle function, and is being investigated for a whole lot more. The researchers suggest that perhaps synthetic mitochondrial DNA could be custom-designed to replace the defective genes and stop tumours and other diseases from developing. "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."
We report that tumor cells without mitochondrial DNA (mtDNA) show delayed tumor growth, and that tumor formation is associated with acquisition of mtDNA from host cells. This leads to partial recovery of mitochondrial function in cells derived from primary tumors grown from cells without mtDNA and a shorter lag in tumor growth. Cell lines from circulating tumor cells showed further recovery of mitochondrial respiration and an intermediate lag to tumor growth, while cells from lung metastases exhibited full restoration of respiratory function and no lag in tumor growth. Stepwise assembly of mitochondrial respiratory (super)complexes was correlated with acquisition of respiratory function.
Our findings indicate horizontal transfer of mtDNA from host cells in the tumor microenvironment to tumor cells with compromised respiratory function to re-establish respiration and tumor-initiating efficacy. These results suggest pathophysiological processes for overcoming mtDNA damage and support the notion of high plasticity of malignant cells.