A while ago, when I was looking through various publications from Chowdhury, I found this one: Prostate cancer cells over express mtG3P dehydrogenase. That's interesting. Why?
Normal prostate cells are special. They don't do the TCA. Glycolysis is fine. Pyruvate conversion to citric acid is also fine. Aconitase is not. Aconitase is deliberately inhibited by Zn retention and the citric acid of the citric acid cycle, which cannot be further metabolised in the said cycle, is then exported in to the prostatic fluid. In large amounts. Mitochondria are not used (much). This is hardly a recipe for over expression of mtG3P dehydrogenase.
Aside: I'm assuming the citrate is used to fuel the mitochondria of sperm. Simply dropping citrate on to the TCA of sperm looks like adding N2O/petrol injection to a standard saloon car engine. Maximum power output at the cost of maximum stress. Only the fastest get to the egg and only best survive the journey, which seems like a good idea when looking for the sperm with the best nuclear-mitochondrial match for fertilisation... End aside.
If we look at the paper on Zn, the TCA and mitochondria in prostate cancer (PCa) we can see that PCa cells lose Zn induced inhibition of aconitase and take off with a large supply of NADH from the TCA, a smidge of FADH2 through complex II and go towards that metastatic ratio of NAD+/NADH. Of course citrate concentration in semen plummets.
So PCa cells use the TCA and oxidative phosphorylation, ie they use mitochondria, to burn citrate derivatives. Normal prostate cells don't. Prostate cancer cells routinely perform beta oxidation. Not so normal prostate cells.
Equally interesting, as Loda's group point out, Fatty Acid Synthase (FAS) appears to be an oncogene in PCa cells. That, to me, suggests that while some of the citrate may well enter the TCA there is also a net synthesis of fatty acids outside the mitochondria. Fatty acid synthesis is a cytoplasmic process. Exported citrate provides acetyl CoA as the raw material for fatty acid synthesis.
BTW I don't doubt that prostate cells do use fatty acids in combination with "normal" levels of glycolysis, but Liu's fascinating paper here, supporting near exclusive fatty acid oxidation in PCa cells, is a classic example of stacking the deck to prove a point, with subtle transitions in graph labelling between tritiated 2-deoxy-glucose (an inhibitor of glycolysis!) and "glucose". There was no glucose, except the deoxy molecule. Oddly enough, glucose and 2-deoxy-glucose are not the same! While I'm completely accepting of the up-regulation of beta oxidation in this cancer, the near complete shutting down of glycolysis looks like pure artefact. They compare metabolic preference by looking at palmitate depletion from the palmitate-only culture medium, which is normal. Then they looked at 2-deoxy-glucose depletion from the 2-deoxy-glucose medium. The whole point of 2-deoxy-glucose is that, while it can be phosphorylated by hexokinase, further metabolism is completely blocked by the lack of hydroxyl group on the second carbon of the molecule. It may get taken up by cells, but it is never bulk metabolised. So it never gets depleted from the growth medium. Duh. I wonder if they expected this result...
I've also looked at Load's ideas about "futile cycling". This is the concept that acetyl CoA, from beta oxidation of fatty acids within the mitochondria, is exported as citrate to form cytosolic acetyl CoA to be converted to palmitate, which is re-imported in to the mitochondria to provide acetyl CoA to re-export as citrate.... Doesn't make sense to me. If you have functional mitochondria and a functional ETC, why bother if it's futile?
But we have seen something very similar in the past. FAS activation seems to be an important feature of TFAM knock out adipocytes. There is no functional complex I in TFAM knockout cell mitochondria and acetyl CoA provides limited FADH2. Without complex I you need FADH2 to drive the ETC, NADH won't hack it. Converting acetyl CoA from any source repeatedly to palmitate generates significant FADH2 during its re-oxidation. It's cycling, but it's not futile. You get something from it which you cannot normally get from pure acetyl CoA, so long as complex I is dysfunctional. Of course you get horrible levels of NADH too, but...
So you have to ask yourself: Do prostate cancer cells lack complex I? Logic says they must do.
Well, what do you know, Parr et al point out:
"For example, a 3.4∆ associated with PCa, removes the terminal region of ND4L, all of ND4, and nearly all of ND5 (Maki et al., 2008; Robinson et al., 2010)"
ie there is commonly a 3.4kb deletion of mtDNA which codes for a very large chunk of complex I in prostate cancer cells. This deletion, the paper suggests, appears to occur BEFORE the cells convert to aggressively cancerous forms.
So what cripples complex I? Well you could make all sorts of guesses about this, especially if you are a lipophobe. There is no doubt elevated free saturated fatty acids, in the presence of hyperglycaemia, will drive completely unreasonable numbers of electrons the wrong way through complex I and a great deal of collateral damage might well result from this process. If you have elevated FFAs you would be insane to raise your blood glucose level. "That's Mr Potato Head to you" (Toy Story 1).
How about simple hyperglycaemia? If you can generate enough free radicals from hyperglycaemia to induce some mitochondria functional you are then in a position to start using those mitochondria. Feeding through mtG3P dehydrogenase's FADH2 to the CoQ couple, while the NAD+/NADH ratio is horribly low from glycolysis, allows plenty of reverse electron flow when you really don't want it. For neurons, which don't do a great deal of beta oxidation, this is my guess for the extensive oxidative damage to complex I seen in PD and AD. Loss of complex I in a neuron, which doesn't do beta oxidation, is going to be disatrous. But in prostate cancer cells? Completely unreasonable superoxide generation appears to trash the mtDNA, as Parr pointed out. Conversion of citrate to fats allows survival under these conditions.
Now let me see, what did Chowdhury say about PCa cells and mtG3P dehydrogenase?????????? Up-regulated is the word. No cell is going to produce mtG3P dehydrogenase without functional mitochondria (and glycolysis) and mtG3P dehydrogenase bypasses a broken complex I, in a similar manner to electron transferring flavoprotein dehydrogenase does. Hyperglycaemia is an interesting concept for generating this cancer.
So....... Do PUFA, particularly omega 3 PUFA, give you prostate cancer? As per the suggestion from the observational association here. Probably not. No more than butter or FAS-produced palmitate give you prostate cancer. But PUFA are really quite special, certainly once the damage is done. They supply significantly less FADH2 input to the electron transport chain per molecule than saturated fats do under beta oxidation conditions, omega 3 PUFA being significantly worst than omega 6 PUFA. So here we have specific fats behaving as suppliers of NADH in rather higher amounts than saturated fats do and FADH2 in rather lower amounts. We have a lack of complex I in PCa cells, so supplying NADH is a recipe for metastasis and a poor fuel for the electron transport chain... In PCa cells acetyl CoA from PUFA is a sitting duck for export as citrate with conversion to palmitate and re-beta oxidation, to maximise FADH2 production. Oxidation of omega 3s via acetyl CoA and its subsequent synthesis and re oxidation as palmitate is not futile.
I have no issue with omega 3 fatty acids as signalling molecules, we clearly need some. I would be very cautious about bulk omega 3s, as I would about bulk omega 6s, as a source of calories.
We are looking here at a potential survival/growth mechanism in the behaviour of cells with severely damaged mitochondria, using any pathway they can to generate ATP. But thinking that it was the the omega 3 PUFA which broke the mtDNA in the first place might be a big mistake. Hyperglycaemia appears to be a far better recipe for mtDNA damage through hypercaloric insulin resistance, N-1a, reverse electron flow, etc gone to excess. PUFA are poor generators of FADH2 during beta oxidation so probably don't drive a lot of reverse electron transport through complex I. And never forget that even the bête noire of fatty acids, palmitate, is harmless in the face of normoglycaemia despite being an excellent generator of FADH2 and reverse flow.
Finally, Parr's group consider the damaged mitochondrial genome to be en-route to a situation where apoptosis becomes very difficult:
"As deletion-driven mtgenome depletion advances, cells become more resistant to cell death stimuli, in comparison to their parental cell lines (Cook and Higuchi, 2012), allowing proliferating cells to escape apoptotic control."
One step towards immortality for PCa cells, excepting the unfortunate destruction of their host organism.