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I don’t get it. Why would decreasing the function of mitochondria be a good thing? Can anyone explain?

klipklop 2y ago
It would indeed be bad if it was systemic. The link seems to suggest it's only certain cells that have influence over blood sugar (the gut, liver, etc).
- fellowmartian 2y ago
  An alternative explanation would be that creates mitochondrial stress that is in beneficial in some ways, maybe similar to Zone 2 training?
dinfinity 2y ago
I also did not understand why it would lower blood glucose, but that is due to my lack of understanding cells. I asked some help from ChatGPT and got this info: "Inhibiting a mitochondrial complex (e.g. one of the electron transport chain complexes) would decrease a cell’s ability to generate ATP through oxidative phosphorylation. As a result, cells would rely more heavily on glycolysis to meet their energy needs, which increases their consumption of glucose. This heightened glycolytic flux leads to higher glucose uptake from the bloodstream and a corresponding drop in blood glucose levels. [...] Cells generally prefer using oxidative phosphorylation (the mitochondrial pathway) over glycolysis to generate ATP because it is more energy-efficient. Oxidative phosphorylation can produce around 30-36 ATP per glucose molecule, while glycolysis alone only nets about 2 ATP per glucose." (Standard disclaimers as to LLM hallucinations apply)
- garganzol 2y ago
  > "This heightened glycolytic flux leads to higher glucose uptake" This is a dubious statement. While glycolysis indeed consumes glucose, the amount of that consumption is expected to be significantly lower than through oxidative phosphorylation. For example, if you deprive cells from oxygen, oxidative phosphorylation gets inhibited and glycolysis kicks in as an alternative metabolic pathway. As a result, blood glucose level goes through the roof. This is what can be seen in patients with acute respiratory distress syndrome. But it is more complicated than that - when oxygen level drops, the nervous system starts gluconeogenesis as an attempt to compensate for the lack of oxygen by increasing the levels of glucose in the bloodstream. So we have multiple parallel effects going on: lower glucose consumption by oxidative phosphorylation due to the lack of oxygen + higher glucose consumption by glycolysis + higher glucose injection via gluconeogenesis. The net result of that formula is that blood glucose level goes up for almost all patients with hypoxemia. Still, glycolysis alone cannot explain the effect of metformin. If it was really a glycolysis with such an amplitude caused by metformin intake, people would start to develop lactic acidosis, air hunger, cellular damages, neuropathy, dementia, cancer. Honestly speaking, the only viable explanation so far is that metformin may cause mitochondria training by mildly and temporary putting a strain on ETC. Like a mild physical activity would do. Anything more impactful than "mild" would lead to an excessive oxidative stress, cellular damages, air hunger, suffocation, and tons of dangerous consequences. Some papers also claim that metformin inhibits gluconeogenesis thus lowering glucose levels, which is another argument in favor of the "biochemical training by metformin" theory. Mitochondria seem to become more robust after a mild stress environment created by metformin, as if you visited a gym.
- chasil 2y ago
  This is interesting in that cancer cells rely more strongly on glycolysis. I wonder if this effect results in more waste products, and if autophagy can reverse it.
byyoung3 2y ago
cells can only divide so many times.
nonameiguess 2y ago
Sounds like it's exactly the same "magic" as exercise and calorie restriction. If the body has more energy available than it needs for normal function, it'll use as much as it can and eventually that use goes to things like general inflammation, cancer, and autoimmune disease. If you use available energy to exercise, simply eat less, or disrupt your body's ability to actually use all the excess food you feed it with drugs, then it won't be able to do those bad things and will only maintain essential function. Obviously, if you restrict too much, you starve. Animals in a state of nature seem to automatically find the right balance and eat roughly exactly what they need. Animals placed into situations in which food is nearly costless, effectively infinite, and you don't need to be active except to the extent you do it freely for recreation, seem to struggle. Humans suffering from diseases of civilization are one such example, but human pets and livestock seem to have the same problems. Presumably, lab rats are basically like that, too. Life in a plastic cage with no predators and food given to you directly by gods is not very similar to life in the wild.
tim333 2y ago
It lowers the level of glucose in the blood. For certain conditions such as some cancers mentioned in the article the low glucose harms the cancer more than the regular cells.

It would indeed be bad if it was systemic. The link seems to suggest it's only certain cells that have influence over blood sugar (the gut, liver, etc).

fellowmartian 2y ago
An alternative explanation would be that creates mitochondrial stress that is in beneficial in some ways, maybe similar to Zone 2 training?

dinfinity 2y ago

I also did not understand why it would lower blood glucose, but that is due to my lack of understanding cells. I asked some help from ChatGPT and got this info: "Inhibiting a mitochondrial complex (e.g. one of the electron transport chain complexes) would decrease a cell’s ability to generate ATP through oxidative phosphorylation. As a result, cells would rely more heavily on glycolysis to meet their energy needs, which increases their consumption of glucose. This heightened glycolytic flux leads to higher glucose uptake from the bloodstream and a corresponding drop in blood glucose levels. [...] Cells generally prefer using oxidative phosphorylation (the mitochondrial pathway) over glycolysis to generate ATP because it is more energy-efficient. Oxidative phosphorylation can produce around 30-36 ATP per glucose molecule, while glycolysis alone only nets about 2 ATP per glucose." (Standard disclaimers as to LLM hallucinations apply)

garganzol 2y ago
> "This heightened glycolytic flux leads to higher glucose uptake" This is a dubious statement. While glycolysis indeed consumes glucose, the amount of that consumption is expected to be significantly lower than through oxidative phosphorylation. For example, if you deprive cells from oxygen, oxidative phosphorylation gets inhibited and glycolysis kicks in as an alternative metabolic pathway. As a result, blood glucose level goes through the roof. This is what can be seen in patients with acute respiratory distress syndrome. But it is more complicated than that - when oxygen level drops, the nervous system starts gluconeogenesis as an attempt to compensate for the lack of oxygen by increasing the levels of glucose in the bloodstream. So we have multiple parallel effects going on: lower glucose consumption by oxidative phosphorylation due to the lack of oxygen + higher glucose consumption by glycolysis + higher glucose injection via gluconeogenesis. The net result of that formula is that blood glucose level goes up for almost all patients with hypoxemia. Still, glycolysis alone cannot explain the effect of metformin. If it was really a glycolysis with such an amplitude caused by metformin intake, people would start to develop lactic acidosis, air hunger, cellular damages, neuropathy, dementia, cancer. Honestly speaking, the only viable explanation so far is that metformin may cause mitochondria training by mildly and temporary putting a strain on ETC. Like a mild physical activity would do. Anything more impactful than "mild" would lead to an excessive oxidative stress, cellular damages, air hunger, suffocation, and tons of dangerous consequences. Some papers also claim that metformin inhibits gluconeogenesis thus lowering glucose levels, which is another argument in favor of the "biochemical training by metformin" theory. Mitochondria seem to become more robust after a mild stress environment created by metformin, as if you visited a gym.
chasil 2y ago
This is interesting in that cancer cells rely more strongly on glycolysis. I wonder if this effect results in more waste products, and if autophagy can reverse it.

byyoung3 2y ago

cells can only divide so many times.

nonameiguess 2y ago

Sounds like it's exactly the same "magic" as exercise and calorie restriction. If the body has more energy available than it needs for normal function, it'll use as much as it can and eventually that use goes to things like general inflammation, cancer, and autoimmune disease. If you use available energy to exercise, simply eat less, or disrupt your body's ability to actually use all the excess food you feed it with drugs, then it won't be able to do those bad things and will only maintain essential function. Obviously, if you restrict too much, you starve. Animals in a state of nature seem to automatically find the right balance and eat roughly exactly what they need. Animals placed into situations in which food is nearly costless, effectively infinite, and you don't need to be active except to the extent you do it freely for recreation, seem to struggle. Humans suffering from diseases of civilization are one such example, but human pets and livestock seem to have the same problems. Presumably, lab rats are basically like that, too. Life in a plastic cage with no predators and food given to you directly by gods is not very similar to life in the wild.

tim333 2y ago

It lowers the level of glucose in the blood. For certain conditions such as some cancers mentioned in the article the low glucose harms the cancer more than the regular cells.