Mitochondria: Cell Life, Death and Cancer
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Mitochondria: Cell Life, Death and Cancer
Do we underestimate the power of mitochondria? Might they unlock the key to cancer treatment?
Introduction
It is an overstated fact that the mitochondria are the powerhouse of the cell. We learn about how they carry out respiration, converting glucose magically into carbon dioxide and water, releasing energy (or ATP) in the process. But how do they do this? And how is the role of mitochondria in cell life and death so crucial that it is currently one of the key considerations in cancer research?
The Krebs Cycle
The Krebs cycle is at the heart of the role of mitochondria as the ‘powerhouse of the cell’. Before the Krebs cycle occurs, a process called glycolysis takes place, which is where glucose is broken down in the cytoplasm of the cell, into pyruvate. This does not require oxygen; a fact which will become important later on. The diagram below lays out a very broad overview of the process of glycolysis:
A 6 carbon molecule of glucose is phosphorylated (adding phosphate), to form a 6 carbon sugar diphosphate (the phosphate comes from the conversion of adenosine triphosphate into adenosine diphosphate).
The 6 carbon sugar diphosphate splits into two 3 carbon sugar phosphates, which each release an electron, converting NAD+ to NADH, whilst the sugar phosphates form pyruvate molecules.
The pyruvate molecules will then go on to take part in the Krebs cycle, or be converted to lactate.
To take part in the Krebs cycle, the pyruvate must enter the mitochondrial matrix, which is enabled by the following pathway:
Pyruvate is converted to acetylCoA, by CoenzymeA being added to the pyruvate. This comes from the conversion of NAD+ to NADH.
The CoA allows the acetylCoA to enter the mitochondria, where it is combined with oxaloacetate, to form citrate.
Citrate is a stage in the Krebs cycle, which is a series of transformations, producing in total:
4 x carbon dioxide
6 x NADH
2 x FADH2
2 x ATP
The NADH and FADH2 release electrons in the electron transport chain, ultimately resulting in the creation of ATP by ATP synthase in the mitochondria.
As ATP is the energy currency of the cell, the Krebs cycle essentially facilitates the generation of energy, which is used by the cell to carry out its various functions.
Mitochondrial DNA and Cancer Treatment
As we have seen, normal cells derive energy from the Krebs cycle. However, cancerous cells can develop into tumours by the production of lactate, disrupting the Krebs cycle. This is known as the Warburg effect, and lactate can induce immunosuppression, further allowing the tumour to grow. As the production of lactate from glucose does not require oxygen, the cancerous cells can divide extremely rapidly, regardless of the oxygen being delivered to it in the blood.
Mitochondria are responsible for apoptosis, which is programmed cell death - an essential element of preventing the growth of cancerous tumours. However, it emerged that around 60% of tumours have shown mutations in mtDNA (mitochondrial DNA), which leads to cancer cells inactivating their mitochondria, allowing the cancerous cells to reproduce infinitely. This led to the interest in the drug called dichloroacetate (or DCA). DCA is very similar to some of the chemical products in the Krebs cycle, and thus can induce a cancerous cell in the lab to carry out the Krebs cycle, reactivating the mitochondria, so that the cancerous cells stop multiplying. Luckily, as heathy cells have properly functioning mitochondria, DCA has no effect on them. DCA was found to be effective in treating certain metabolic disorders, and in decreasing the size of cancerous tumours in rats. It has also passed various security tests. On the other hand, DCA has been found to induce cancer in some animals, and is also classified as an environmental pollutant.
Another exciting manifestation of the importance of mitochondria in the development of a cancerous tumour is the research of Cancer Research and Biotechnology AG, a Swiss preclinical biotechnology company, who is looking at the development of small molecule drugs which can impact the tumorigenic mitochondrial dysfunctions involved in the development of cancer.
Clearly, mitochondria have the potential to offer a way in, on the scene of cancer treatment, due to their role in the Krebs cycle, and apoptosis. Perhaps one day, we will be taught that mitochondria were the miracle we harnessed in cancer treatment, rather than the powerhouse of the cell.
Bibliography:
https://www.mdpi.com/2072-6694/13/13/3311
https://www.youtube.com/watch?v=JOncWQUpMzc
https://royalsocietypublishing.org/doi/10.1098/rsob.200061
https://news.cancerresearchuk.org/2021/05/05/mitochondrial-dna-in-cancer-small-genome-big-impact/
https://news.cancerresearchuk.org/2010/05/12/potential-cancer-drug-dca-tested-in-early-trials/