Monday, January 13, 2014
Mitochondria to the rescue
Yes, I confess I'm quite fascinated by mitochondria. Not only their well functioning seems to be correlated to lifespan, like I discussed last time, but it's also implicated in cancer.
Briefly, last post taught us that mitochondria provide energy to the cell by producing ATP through four different oxidative complexes. However, mitochondria's oxidative activity wanes with age. Researchers found one pathway in particular that is activated in low-fat diets and high-exercise regimens, which can reverse the decrease in oxidative activity.
In 1926, a German physician named Otto Warburg discovered that, contrary to healthy cells, which produce ATP through the mitochondria oxidative complexes, cancer cells produce most of their ATP through a process called glycolisis. Glycolisis can be thought of, in lay-man terms, as fermentation of sugar. Thanks to this discover, which was confirmed across many different lines of cancer cells, Warburg was awarded the Nobel Prize in 1931. Warburg hypothesized that the underlying cause of cancer was a dysfunction in the mitochondria that led to upregulation of glycolysis.
If glycolysis is a hallmark of cancer, can it be used to target cancer cells and destroy them, while leaving the healthy cells untouched? Furthermore, can we "cure" cancer cells by restoring the mitochondria oxidative complexes?
The answer to the second question appears to be no: while it is true that mitochondrial activity slows down in cancer cells, this is not always due to mitochondrial dysfunction, rather, to disruption in signaling pathways that regulate glucose uptake and production. As the word suggests, the oxidative complexes in the mitochondria produce ATP using oxygen, whereas glycolysis produces ATP without the use of oxygen. The upregulation of glycolysis could be an adaptation of tumor cells due to their fast proliferation. Healthy cells receive oxygen through blood vessels. However, tumor cells outgrow the production of new vessels and therefore, in order to survive, they have to adapt to the absence of oxygen. Normally the absence of oxygen would lead to cell death, which is regulated by the p53 protein. As it turns out, p53 is either mutated or downregulated in tumor cells.
So, what does the Cell paper on aging teach us about cancer?
Remember that when it comes to cells, there's never an on/off switch, but rather a cascade of signals, i.e. chemicals that activate one another sort of like in a domino effect--what we call a "pathway." To reconstruct a pathway you have to look at each domino piece and how they interact with one another. That's why things get a bit complicated.
The upregulation of glycoysis happens through a protein called hypoxia-inducible factor-1, or HIF-1alpha. HIF-1alpha is a transcription factor, in other words, a protein that binds to DNA and regulates the expression of certain genes. Gomes et al.  found that HIF-1alpha induces some kind of metabolic reprogramming, not just in cancer cells, but also in normal tissue as a consequence of aging. Previous studies have shown that a high-fat diet increases levels of HIF-1alpha in the liver.
In , Gomes et al. induced a decline of mitochondrial activity in mice by knocking out the SIRT1 gene, a gene that codes for a protein called Sirtuin 1. It turns out, without SIRT1, not only did the researchers see the decline in mitochondrially encoded oxidative complexes, but they also observed high levels of HIF-1alpha and high expression levels of the genes targeted by HIF-1alpha. Gomes et al. restored expression of SIRT1 using a molecule called NAD+, thus restoring mitochondrial activity and lowering again the levels of HIF-1alpha. It would be interesting to see if this molecule could be used in cancerous cells as well, and if downregulating glycolysis would eventually kill the cancer cell given that they have to grow in a low-oxygen environment.
 Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, & Sinclair DA (2013). Declining NAD(+) Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging. Cell, 155 (7), 1624-38 PMID: 24360282