Interfering with mitochondrial dynamics causes cancer (by driving inflammation); no carcinogen/mutation required!

[haidut]

One of the rare studies that quietly lets the truth out in the open. Namely, that cancer is a metabolic/inflammatory disease that does not need any oncogenic mutations to occur first. All that is needed is a process that interferes with mitochondrial dynamics (fission/fusion), which then drives chronic inflammation in the cell, and finally cancer forms spontaneously! Unsurpisingly, the process that interfered with the mitochondrial dynamic was linked to elevated fatty acid oxidation (FAO). Conversely, blocking the inflammatory pathway resulting from suboptimal mitochondrial dynamics virtually arrests further cancer development. I wonder how long before that study gets retracted for “unspecified” reasons…

https://egastroenterology.bmj.com/content/4/2/e100408

Why Some Heavy Drinkers Grow Giant Mitochondria That Guard the Liver, for a While

“…And the surprise was what those giants could do. Using bench techniques that measure how hard a cell is breathing, plus a sweep of the liver’s metabolites, the researchers saw alcohol-fed mice ramp up oxygen consumption, push out more NAD+ (the molecule alcohol notoriously drains), and burn fat more efficiently. Not the picture of a poisoned cell at all. ”

“…The trouble is that the defence has a shelf life. New megamitochondria help; old ones turn on their host. As the giants persist, they take on damage, mutated mtDNA, broken proteins, and they can’t be cleared away. Mitophagy, the cell’s housekeeping system for junking spent mitochondria, needs them chopped small first, and these are far too big to swallow. So the damaged hulks pile up. Worse, they start leaking their own DNA into the cell’s interior, where it trips an ancient alarm system called cGAS-STING that’s meant to detect invading viruses. The liver, in effect, mistakes its own broken machinery for an infection and lights a slow inflammatory fire, the kind that scars tissue into fibrosis over years. To see what losing fission really does, the team engineered mice whose liver cells lack DRP1 entirely. These animals developed elevated liver enzymes, fibrosis, and, by 12 to 18 months, spontaneous liver tumours. No carcinogen required; jamming the [mitochondrial] dynamics was enough on its own.”

“…Then came the genuinely counterintuitive bit. You might assume the fix would be to restore fission, get the scissors working again. Instead the researchers knocked out the fusion machinery too, both mitofusins, MFN1 and MFN2, on top of DRP1. With neither side of the cycle running, the mitochondria settled into a kind of frozen equilibrium the team calls mitochondrial stasis. And these triple-knockout mice fared markedly better: less injury, less fibrosis, fewer tumours, whether the cancer arose spontaneously or was provoked by oncogenes. The cGAS-STING alarm, blaring in the DRP1-only mice, fell almost silent. Delete the cGAS sensor directly and the tumours dwindled too, which nails the inflammatory pathway to the cancer rather than leaving it a bystander. There was a metabolic tell, as well. The DRP1-deficient livers showed a buildup of dihydroorotate and orotate, intermediates in the manufacture of pyrimidines, the raw nucleotides a cell needs to copy its DNA and keep dividing. Exactly the sort of supply line a growing tumour wants. In the stasis mice, that signal was blunted.

Via: https://haidut.me/?p=3102

[yerrag]

@haidut

I am wondering if it is really inflammation that is causing mitochondrial dysfunction and not the other way around.

I have a large store of bacteria that I keep having to kill and each time there is a kill plenty of endotoxins are released and they are a major source of inflammation. And it suppresses mitochondrial activity to the point that even the conversion of cholesterol to pregnenolone and downstream prosuction of hormones and steroids are very much affected.

To such effect that taking hormones like thyroid and pregnenolone and progesterone can hardly make a dent.

I had to inhibit the nfkb inflammatory response using turmeric and black pepper in order to see my cholesterol level go down and my hormonal production go up.

But it is hard to keep endotoxins low when there is a large colony of pathogenic microbes and in my case it is feom periodontal infection having translocated to my vascular and lymphatic system where it get more embedded over time especially as it gets protected by biofilms.

One way I see out of this conundrum of killing pathogens by relying on our endogenous ROS from our own innate immune system and from use of pharma antibiotics or herbal antibacterials,, which all end up producing endotoxins; is to engage antibacterial peptides such as LL-37 in neutrophils and macrophages - to kill pathogens with the benefit of not leaving behind endotoxins that both inflame and cause oxidative stress.

More sunshine to produce high levels of Vitamin D (50-80 ng/dl) together with plenty of butyric acid in the gut gives the body a high endogenous supply of LL-37 to achieve effective antimicrobial activity without endotoxic side effects.