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Mitochondria may hold keys to anxiety and mental health (quantamagazine.org)
277 points by jger15 on Aug 12, 2020 | hide | past | favorite | 161 comments



> The organelles are ancient invaders — the remnants of symbiotic bacteria that integrated themselves into host cells about 2 billion years ago and specialized for energy production.

That's accepted as scientific orthodoxy now, but it wasn't always. In the 1960's, evolutionary biologist Lyn Margulis proposed the theory that cell organelles such as mitochondria and chloroplasts were once independent bacteria, which combined through symbiotic mergers of bacteria to evolve into eukaryotic cells. Ernst Mayr called this "perhaps the most important and dramatic event in the history of life".

Throughout her career, Margulis' work could arouse intense objection. One grant application elicited the response, "Your research is crap, do not bother to apply again", and her formative paper, "On the Origin of Mitosing Cells", appeared in 1967 after being rejected by about fifteen journals.

In 2002, Discover magazine recognized Margulis as one of the 50 most important women in science.

In 1995, Richard Dawkins said, "I greatly admire Lynn Margulis's sheer courage and stamina in sticking by the endosymbiosis theory, and carrying it through from being an unorthodoxy to an orthodoxy. I'm referring to the theory that the eukaryotic cell is a symbiotic union of primitive prokaryotic cells. This is one of the great achievements of twentieth-century evolutionary biology, and I greatly admire her for it."


How is the research going on the effects of antibiotics on these organelles?


That's a great question. A lot of antibiotics are effluxed out so they don't build up to high levels within the cell. Also, a lot of antibiotics bind to part of the bacterial cell wall, which mitochondria lost over evolution. Antibiotics that inhibit protein synthesis actually do negatively impact mitochondrion but not as bad because of divergences in ribosomal structure compared to bacteria.


She's a victim of Nobel Disease and said stupid things out of her field. How is that controversial?


[flagged]


I mean... maybe, but probably not. Science has also learned a lot since then, and most skeptics aren’t scientists. Plausible cynicism grade: C-


Every scientist should be skeptical. Doesn't mean he should join some skeptics movement.


I meant to put skeptics in scare quotes. It could also be replaced with “self-described skeptics”.


Based on the debate currently raging over hydroxychloroquine and its uses/effectiveness I can totally imagine the typical Twitter reaction being of rather poor quality.


Is there any scientific consensus/studies showing hydroxycloriquine as effective?

As far as I know, the biggest impact right now seem to be: anti-clotting medication, steroids, turning the patient on his belly and avoiding intubation for as long as possible.


The thing is you need people spreading ideas against the consensus because if they're good they might become part of the consensus. The consensus was very much against the public wearing masks in early March and against steroid use until fairly recently.


And both of those things are now considered valid approaches due to research establishing that, not because random celebrities promoted them on twitter.

Health authorities didn't change recommendations on masks and dexamethasone due to twitter lobbying; they changed them because evidence emerged that they were safe and and least somewhat effective.


As of right now, I believe the general consensus is that it's not effective (or at least not more effective than standard treatment). However, if you went back just a few weeks you'd have seen quite a few credible people claiming it could very well be a gamechanger. It says something that Trump was taking it, because even if you dislike the man it's hard to imagine there is any other human being on the planet with greater access to the world's best doctors and whatever bleeding edge technology could be used.

That said, I was really highlighting a recent example of how poor communication is, and how fast opinion can shift.


> As of right now, I believe the general consensus is that it's not effective (or at least not more effective than standard treatment). However, if you went back just a few weeks you'd have seen quite a few credible people claiming it could very well be a gamechanger.

I'm sorry, does this address the comment at all? There was indeed, this spring, real scientific debate over the potential efficacy of hydroxychloroquine. But the raging Twitter wars over it did not constitute that debate.


No need to be sorry!

I was asked if there's consensus regarding the effectiveness of HCQ. Currently, there is not. Not long ago, medical professionals were recommending it and there was, at least publicly, a consensus of sorts based on the positive results of early studies.

I then pointed out how fast consensus shifted from 'this stuff is awesome' to 'this stuff is stupid' because I believe it's relevant for anyone trying to formulate their own opinion about how solid that consensus really is.

The twitter wars and the general terrible communication online is a totally separate topic, and the one I was originally commenting on because /u/gbrown seemed to have a more positive outlook than I do on the subject.


I mean, he probably has unparalleled access to the world's greatest mechanical and hydrological engineers if he wants it, but still seems noticeably confused about how toilets and dishwashers behave. The issue with Trump isn't that he doesn't have access to expertise; it's that he ignores it.


[flagged]


> Didn't Trump recommended people drink or inject bleach?

No, he didn't, listen to what he actually said.

https://www.youtube.com/watch?v=33QdTOyXz3w

It's not a claim, it's an arguably stupid question to some guy off-screen. Yet, the title of this video is "President Trump claims injecting people with disinfectant could treat coronavirus". The outlet is the presumably reputable "Telegraph".

Trump also never called Nazis "fine people". What actually was said:

"...you had very fine people on both sides..."

https://www.youtube.com/watch?v=JmaZR8E12bs&feature=youtu.be...

"And you had people - and I’m not talking about the neo-Nazis and the white nationalists - because they should be condemned totally."

https://www.youtube.com/watch?v=JmaZR8E12bs&feature=youtu.be...

The job of the media is to fabricate outrage and scandals, because that's how you get attention. Trump doesn't even mind, in fact he is taking advantage of it:

https://growth.me/book-summaries/art-of-the-deal/#3-being-bo...

Remember when he "accidentally" mistook WWI for WWII in some press conference? The headline: "Another dumb thing that Trump said!"

However, it's a mistake that anybody - particularly average Joe - could've made. It's not really that negative, in fact it could be endearing to some people.

More importantly though, that headline is going to take attention away from actually negative news, such as "over a thousand American Coronavirus deaths occuring every day".

So, if you think Trump is really that stupid, maybe you're not really that smart.


No he didn't, you fell victim to the fake news media.

During one of the press conferences, he asked some scientist or doctor guy if disinfectants can kill viruses on surface, would it be possible to create an injection that works like a disinfectant cleaning the body. He never said people should do that on their own.


The issue with hydroxychloroquine is that claims of effectiveness without evidence, particularly as a prophylactic, cause an immediate public danger (particularly given its promotion by certain public figures in an irresponsible manner; see "what have you got to lose?") This isn't purely theoretical; people have self-medicated and died.

At any given time there are thousands and thousands of unproven drugs under development or being evaluated for new applications. There are even many possible covid treatments being evaluated without similar controversy, because no-one with a large audience has suggested self-medication.

Hopefully the hydroxychloroquine thing is a one-off, and public figures will be more careful in future about public promotion of unapproved drugs. It would be extremely dangerous, and damaging to legitimate scientific investigation, if this sort of thing becomes common.


Well, I assume that along with her would also be a bunch of genuine cranks, mystics, "skeptics" etc. She'd be collateral damage.

Similar case that springs to mind is the chap who had to infect himself to prove that stomach ulcers were caused by bacteria.


Barry Marshall can just wave his Nobel prize at any skeptic.

https://www.nobelprize.org/prizes/medicine/2005/press-releas...

Lyn Margulis did not and will not ever have that pleasure, because, like Rosalind Franklin, (a) she was female, and (b) she's now dead.


[flagged]


I'm being downvoted for simply pointing out that there was/is a public 'debate' (if we can even give it that much credit) about hydroxychloroquine, and that the current state of online communication makes me able to imagine similar reactions to Lynn Margulis's work.

I wouldn't take it personally, anything political on this forum seems to experience high variance.


I don’t mind. It’s an expression of the mind of the moderator. I like to try to guess their age and gender. But they are invisible so I don’t get any confirmation.

I like this Hacker News. The discourse is civil and often informative.


... Eh, no.

General rule: controversial theories, in a vacuum, are fine.

Promoting controversial theories in a manner likely to lead people to die (hydroxycloroquine self-medication, bleach-drinking, deliberate self-infection): not fine.

Twitter and Youtube are full of people promoting all sorts of nonsense, and also legitimate unorthodox theories (there is a difference; there's a huge gap between, say, "the earth is flat" and "dark matter isn't a thing") without any trouble. It's when you get into the realm of health advice that is likely to injure people that there's a problem.


After all, Twitter mobs love nothing better than pouring through the annals of biology journal?


That should be "poring through", I think. (It's not an easy one to remember.)


For Twitter mobs I'd go with pawing through.


> These days she'd have angry Twitter mobs doxxing her for opposing the "scientific consensus", or YouTube shutting down her account for spreading "misinformation".

I would assume that this incredibly smart scientist (for all her HIV and 9/11 bonkers and disgusting lunacy) would not be using Twitter as the medium for her scientific discussions.

I'm fascinated by how especially conspiracy theory people equate fighting on Reddit/Twitter/YouTube/… with real scientific debate.


Haha probably true.


Sadly, these days Lynn Margulis is better known for her AIDS crankery:

> Margulis said that "the set of symptoms, or syndrome, presented by syphilitics overlaps completely with another syndrome: AIDS," and also noted that Kary Mullis[a] said that "he went looking for a reference substantiating that HIV causes AIDS and discovered, 'There is no such document.' "

> This provoked a widespread supposition that Margulis had been an "AIDS denialist." Notably Jerry Coyne reacted on his Why Evolution is True blog against his interpretation that Margulis believed "that AIDS is really syphilis, not viral in origin at all."[50] Seth Kalichman, a social psychologist who studies behavioral and social aspects of AIDS, cited her 2009 paper as an example of AIDS denialism "flourishing",[51] and asserted that her "endorsement of HIV/AIDS denialism defies understanding."[52]

Also: 9/11 crankery!

> Margulis argued that the September 11 attacks were a "false-flag operation, which has been used to justify the wars in Afghanistan and Iraq as well as unprecedented assaults on ... civil liberties." She claimed that there was "overwhelming evidence that the three buildings [of the World Trade Center] collapsed by controlled demolition."[5]

https://en.wikipedia.org/wiki/Lynn_Margulis


The complication with (incorrectly) labeling Margulis "an AIDS denialist", msla, is that you then make her responsible for a whole collection of unsubstantiated tropes that are targeted by that label. That's unwarranted, because Margulis was doing something quite opposite to "AIDS denialism"; Margulis, an esteemed scientist, was proposing an alternative causative factor that may explain AIDS, which isn't HIV, or more precisely, which isn't HIV in isolation.

This fascinating discussion will make your jaw drop https://www.discovermagazine.com/the-sciences/discover-inter...


> Margulis, an esteemed scientist, was proposing an alternative causative factor that may explain AIDS, which isn't HIV, or more precisely, which isn't HIV in isolation.

She's not esteemed in the field of what causes AIDS. She's esteemed in a different sub-field. In terms of AIDS, the actual experts have come to the conclusion she's wrong, and one thing we should all have learned by now is that our ignorance is not equal to the knowledge of experts.

> This fascinating discussion will make your jaw drop

Not for the reasons you think it would, though.


>She's not esteemed in the field of what causes AIDS. She's esteemed in a different sub-field. In terms of AIDS, the actual experts have come to the conclusion she's wrong, and one thing we should all have learned by now is that our ignorance is not equal to the knowledge of experts.

The history of science also told us by now that experts are stubborn, and sometimes they have to first die, for the next generation to accept another theory.

It has also taught us that important new discoveries more often than not come not from established experts in a field, but by people from another sub-field or another field all together...

It has also taught us that scientists should continue challenging prevailing hypotheses all the time, because that's part and parcel of doing science...


> The history of science also told us by now that experts are stubborn, and sometimes they have to first die, for the next generation to accept another theory.

It tells us too that cranks will be cranks regardless of the evidence against them, and that cranks are more common than true revolutionaries.


Exactly. An “expert” is a skilled practitioner of some domain of human endeavor; a scientist is a truth-seeker. Expertise is orthogonal to scientific truth.


> Expertise is orthogonal to scientific truth.

Expertise is the result of successful scientific seeking.


Not seeing how these two are connected, equivalent, etc


I am disabled with Anxiety and Mood Disorder and chronic fatigue/depression. Typical "Bipolar" presentation. It runs in my family on my mothers side. We also have a history of early (45 years old) heart disease.

So I knew this was mitochondrial but it was revealed when I received my genome. We have issues with our electron transport chain; Complex I (ND1 and ND4) and Complex III (MT-CYB).

So diet and lifestyle was crucial in getting me off all of my meds, and I was on a lot. High dose riboflavin was a huge help.

Getting complex I to work well helps with the heart since it increases NAD. Also getting enough ubiquinone from diet helps. I get it mostly from seafood like Salmon and Liver. I might try and take a CoQ10 supplement soon. But the fact that we make it endogenously makes me think it is not needed. Statins will stop the production of CoQ10 by lowering FPPP production which is why they fail to help people with Heart Disease.

Balancing the flow and the oxidative stress from the mitochondrial electron transport chain is crucial.


> Statins will stop the production of CoQ10 by lowering FPPP production which is why they fail to help people with Heart Disease

I would like to know more about this. I've been on a statin for several years and feel like my energy has dropped through the floor in that time. I also feel like I have a 'statin hangover' when I wake up in the morning (I usually take it with my supper). This could all be correlation, and aside from cholesterol levels I haven't been diagnosed with heart disease. But I would like to know more, because I hate taking this stuff and really don't like the idea of being on it the rest of my life.


This is pretty much all you need to know:

https://ubiquinol.org/sites/default/files/statins.gif

The thinking on cholesterol and heart disease is changing rapidly and there really is no strong evidence high cholesterol before a heart attack leads to any bad outcomes. After a heart attack, statins are ok.

But like we see, side effects. My doc wanted me on them but they gave my mother horrible myopathy so I passed. My HDL was really low until I took out all plant oils and eat fats pretty much only from fish and olive oil. Now my HDL in mid range normal. This is becasue the omega 3 helps with reverse cholesterol transport.

But again, this is me and my genetics. We have Saami (Inuit) heritage which is why I think i need this diet.


> I am disabled with Anxiety and Mood Disorder and chronic fatigue/depression. Typical "Bipolar" presentation. It runs in my family on my mothers side.

That sounds awfully familiar. Would you be so kind to provide any starting point to begin research into this, including the supplement stuff you mentioned afterwards?


I would start by getting your full genome run, or at least get it from Ancestry. Then learn how to look at the low frequency SNPs. I am lucky as I live near UNC Chapel Hill that has several departments looking into this stuff.

The supplements came after I saw my genetics and from past anecdotal experiments. But maybe start by understanding the electron Transport chain. When I saw all the oxidative stress created there I began looking at the several pathways for the flow of O2- and H2O2. To me, mood disorders have their root in this flow being unobstructed.

Riboflavin ended up being big for me for several reasons.

Keep in mind, mood disorders are polygenic, may causes, so for you it might be something with Monoamines or what ever.

I wish doctors would get serious about testing for these deficiencies in people wit mood disorders...


Can you tell me which SNPs were relevant for you? Or are generally relevant for depression?

I checked https://www.snpedia.com/index.php/Depression but maybe you know better which SNPs are most important?

I got my genome and checked it using promethease, but 'sadly' I didnt get any major 'depression' hit; only minor SNPs which were correlated with 1.5x more probability to get depression

And I got no advice on which diet could help me :)


I'm in a similar situation. I've found that taking CoQ10 and NAD+ (e.g. Niagen or Elysium Basis) has been helpful.


Did you ever take lithium?


Yes, both carbonate and orate. The carbonate, well that flattened me out of course, but it did not make me feel as good as I do now. (Which is not that good but much much better.)

The ortate I took as an experiment wen I was more recently depressed and it made me hypomanic. This makes sense if you know Lithium inhibits IMPase and IPPase. And on the other side GSK-3.

It is only at high doses that you get the NMDA and GABA effects. Which is too high IMHO. I still rely on Klonopin now and then when I mess up. (No, I do not take it everyday and I take the lowest dose possible, so don't bother telling me how dangerous it is.)


Thank you for your answer.


The article does not really warrant the title. The best evidence seems to be "a meta-analysis of 23 studies on mitochondria and anxiety: 19 demonstrated “significant adverse effects of psychological stress on mitochondria”", but that's the other way around. And there are of course many factors associated with anxiety and other mental health issues that do not seem related to mitochondria.

Nobody is going to deny that a badly functioning component in your body can affect your mental health, and some of the mechanisms sound interesting, but not enough to call mitochondria the "key to anxiety and mental health". It's more like: an easily overlooked factor that can contribute.


I'm surprised that the role of Magnesium isn't discussed as well.

"Mitochondrial Mg2+ homeostasis decides cellular energy metabolism and vulnerability to stress"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960558/

Anecdotally, I've been taking Magnesium l-threonate and it's probably the least anxious I've ever been in my entire life (I'm 42).

The only thing comparable was Lexapro, but I always had a love/hate relationship because of the side effects.


Your opening line made me laugh inappropriately. When I was in grad school in molecular biophysics, someone asked, “if I fall asleep during a talk, and wake up just in time for questions, what question can I ask, to look smart, regardless of the topic of the talk?” The answer? “What was the magnesium concentration?”


I recall a similar story regarding (iirc) programming language type theory: "How does it handle recursion?"


In economics it's "Isn't that endogenous?"


In physics, it's "is it gauge-invariant?"


Better than your concentration.


Haha, I love it!


Magnesium is amazing for many things.

Have several crippling conditions. Magnesium has brought drastic relief.

Muscle aches, migraines, cognitive issues.

Al much improved.


I take Mg and Ca, they work wonders on my anxiety, stress level, sleep and back pains. The combo also increases sex drive. They make me feel half my age.


Username checks... well, close enough


Which product specifically do you use, if you don't mind me asking? I'd like to try it myself to see if it helps me as well.


I use Life Extension's but there's plenty of brands out there. https://www.lifeextension.com/vitamins-supplements/item02032...

I take one scoop, 2-3 a day. Depends on how stressed I am. Always once in the morning. Sometimes in the afternoon (it seems to help my concentration stamina). Once close to bed.

Ruminations have diminished. Anxiety greatly lowered.

I still get sad, angry, etc. But those feelings seem to dissipate much quicker. Mentally I get exhausted less. N=1, of course.

*I also take a calcium/vitamin d/zinc combo as well.


Does it really work fast enough that you could notice a difference if you took it in the afternoon vs not? I thought most vitamins and minerals took days if not weeks to work.


I feel like I noticed a real difference within three days.

I'm open to this being placebo effect.

In the morning especially, my anxiety always seemed to be at its highest. If I took the mg l-threonate before bed, those feelings in the morning just weren't there.


Why supplements instead of dietary, if you don't mind sharing?


AFAIK proper levels of Mg are hard to come by, nowadays. Soils are depleted.


Thanks, made my heart sink but makes sense :-/


Dosing is just easier.


Note that Magnesium deficiency might be a downstream effect of a malfunctioning mitochondria [1]. Taking CoQ10 might help (it did greatly in my case)

  The authors findings demonstrate low brain free [Mg2+] in our patients and indicate that it resulted from failure of the respiratory chain.
[1] https://journals.sagepub.com/doi/pdf/10.1097/00004647-199905...


Did you have success with ubiquinone, or do you use ubiquinol?


I tried ubiquinol, but not worth it in my case. Using a enhanced CoQ10 (q-absorb) does the trick for me. 100mg/day. Also tried up to 600mg/day with no additional benefit


Magnesium L-threonate may have better cognitive than other formulations, but I wonder if a magnesium glycinate formulation would be better for anxiety/stress reduction.

Anectdotally also, I take Magnesium Bisglycinate from Thorne occasionally and it helps me relax and feel less anxious. My muscles stay pretty rigid normally and after taking the magnesium supplement I can feel everything loosen up. Helps with sleep too.


In my specific instance, I have taken both.

I experienced some reduction in anxiety with the glycinate. It also seems to be the best form for sleep support.

But the l-threonate was on the level of an SSRI for me. The anti-anxiety effect was really pronounced.


The article noted that Acetyl-L-Carnitine

> protected mice vulnerable to behaviors associated with depression in humans

Which I'm curious about as well.


Magnesium will reduce ATP Since it is a cofactor for the ATPases. Less ATP means less anxiety.


This is incorrect. Most ATP found in our cells is in the form of MgATP and magnesium is crucial for the regulation of ATP production [1]. ATP levels are tightly controlled within cells and although mitochondria may play a role in psychological disorders [this article][2] simply saying that less ATP means less anxiety is wrong.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960558/ [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997778/


Will this negatively effect strength or endurance of workouts?


What is ATP?


This should be common knowledge, but adenosine triphosphate, the main short-term energy storage and transport medium in a living cell.

https://en.wikipedia.org/wiki/Adenosine_triphosphate


Well, I thought it was Adenosine Triphosphate, but I was surprised that Magnesium reduces ATP.

I interpret that as saying that the more Magnesium you have in your body, the less energy you have. Also, the less energy you have, the less anxiety you feel. That sounds wrong to me, although I can't explain why.

Am I confused? What am I missing?


That's how I interpreted it as well.

This is how I understand the anxiolytic effect of mg works:

>It acts as the gatekeeper for the N-methyl-D-aspartate (NMDA) receptors, which are found on your nerve cells and aid brain development, memory and learning.

>In healthy adults, magnesium sits inside the NMDA receptors, preventing them from being triggered by weak signals that may stimulate your nerve cells unnecessarily.

>When your magnesium levels are low, fewer NMDA receptors are blocked. This means they are prone to being stimulated more often than necessary.

Maybe this is why I experience more rumination without magnesium?

https://www.healthline.com/nutrition/what-does-magnesium-do#...


But that sounds different. It doesn't sound like it reduces the level of ATP, but that it reduces overstimulation.


Oh, yes, I did wonder about that as well. Would like to know more.


Association of Tennis Professionals


What dosage do you take? I've had some results with Magnesium Citrate.


I do 300 to 1200mg elemental magnesium from magnesium diglycinate and magnesium citrate, ethier as mixed powder / tables or separate powders / tablets, daily, spaced morning evening and before bed.

Haven't tried msg l threonate, will order some thing week.

Full disclosure: studied nutritional medicine in a formal capacity.


Besides magnesium, what else is often deficient in nutrition (Vitamin D, etc.)


A lot depends on dietary habits. If you are vegetarian or don't eat much red meat, you might need iron. I take a multivitamin the size of a horse pill and cover my bases with that cocktail, rather than pick and guess.


Which multivitamin do you take? I've been looking for one that covers as much as possible. (I'm on a heavily restricted diet)


I use the pure O.N.E.: https://www.pureformulas.com/one-multivitamin-60-capsules-by... recommended by Dr. Rhonda Patrick, along with Magnesium CitraMate: https://www.thorne.com/products/dp/magnesium-citramate


I use these but I didn't really do much comparison shopping:

https://www.vitaminshoppe.com/p/one-daily-men-multivitamin-1...


Busy at work sorry.

Check back here later, or contact me as per details in my profile.


Note that Magnesium Citrate is often used as a laxative. It's usually an order of magnitude higher amount of magnesium than when you're taking it as a supplement though.

But if you are sensitive to magnesium's laxative effects you may want to look for another formulation.


I heard threonate crosses the brain blood barrier. I was worried about the opposite happening. What brand do you take?


How long did you have to take it before you noticed a difference? Are we talking one per day?


This guy theorized that autism is caused by a problem with ATP and mitochondria. He did a trial of an old, obscure drug that blocks ATP receptors (for signaling, not metabolism) on young ASD patients and there was noticeable improvement in their symptoms. More studies are underway.

http://naviauxlab.ucsd.edu/science-item/autism-research/


>>> obscure drug that blocks ATP receptors

In case you are wondering, Suramin[1] is the drug

[1] https://en.wikipedia.org/wiki/Suramin


For those, like me, who find this article too pseudo-sciencey, the paper Psychological Stress and Mitochondria: A Conceptual Framework [1] lays the foundation I was missing:

> It is also interesting to note in the context of stress regulation that all steroid hormones, including glucocorticoids and sex hormones, are synthesized in a process that is regulated by, and occurs in mitochondria, further linking mitochondrial biology to stress signaling.

Stress in this sense refers to all biological stressors such as physical exertion. Mitochondria, therefore, are not only central to energy production but also to stress response. This is simply how the system works.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901651/


Presumably it's not the mitochondrial DNA itself that is causing the problem but rather chromosomal DNA (or some combination). If it were only mitochondrial DNA then it would be strongly heritable from the mother's side, which is not what we see.


Ha.. my mom is super anxious as was her mom.. and me.. yep!


Yes, I definitely got my depression from my mother's side of the family. But as far as I'm aware, after controlling for environmental factors (such as amount of time spent with each parent, etc) there's no detectable bias toward maternal inheritance.


Fun fact: we still can’t genetically transform human mitochondria, and we’ve tried for decades


What would it mean to “genetically transform” a human mitochondria, and why are have we been trying to for decades?


Mitochondria have their own genome; the parent is talking about editing that genome which has several fairly unique challenges above normal chromosomal DNA editing.

That being said, there were recently some breakthroughs in this area: https://www.nature.com/articles/d41586-020-02094-x


Unfortunately we don’t have anything beyond editing yet :(

We’ve known TALENs can edit for a while, but that breakthrough made it a lot more efficient.


I guess I don't understand the distinction you're making between "editing" and "genetically transforming"?


You can make a base pair edit, but you can’t, for example, add in GFP


Add new DNA into the human mitochondria. If you could do that, you unlock a massive amount of science around how mitochondria function, kinda similar to “what I cannot create I do not understand.

From an engineer’s perspective, mitochondria are kinda the equivalent to virtual machines running on normal computers, as little “virtual cells” within cells. Their genomes are so stripped down that you can do some wild things with them.


> If you could do that, you unlock a massive amount of science around how mitochondria function

Note that 99% of the proteins contained in mitochondria are [coded] in the nucleus, only 1% is [coded] in the mitochondrial chromosome. It's extremely small, only containing 37 genes of which most are related to translation (but of course translation requires far more, e.g. elongation factors).

https://www.nature.com/articles/nrm2959


I guess that was a bit of a hyperbole. You can learn more about the mitochondria genetically engineering the nucleus, but the main problem is that there still is science to be done on the mitochondrial genome that is "locked" down by not being able to transform it, especially when it comes to stuff like how translation works within those mitochondria.


I get what you're saying, but I think you have a typo in there. Most of the proteins in the mitochondria are coded by nuclear DNA, but the proteins themselves end up in the mitochondria.


Thanks! Edited.


The number of genes encoded in the mitochondrial chromosome, 37, reminds me of the 29 states in Von Neumann’s universal constructor [1].

[1] https://en.wikipedia.org/wiki/Von_Neumann_universal_construc...


My answer to this question was ‘A John Scalzi Novel.’

But IIRC weren’t mitochondria subsumed by another cell for ATP output forever ago in our evolutionary development?


yep, and you can even make synthetic endosymbionts! (pretty new science too!)


Can we do this with nuclear DNA?


You can. if you want a new piece of DNA stably inserted into the nuclear genome, you have a couple of options:

https://en.wikipedia.org/wiki/Lentiviral_vector_in_gene_ther...

https://en.wikipedia.org/wiki/CRISPR

These next two do the same thing as CRISPR, only they are older technologies that take you longer to generate the probes in the lab to target your spot in the genome. The real advantage of CRISPR isn't what it does, that was already out there, it's that it's cheap and fast (comparatively) and an undergrad can do the whole experiment.

https://en.wikipedia.org/wiki/Zinc_finger_nuclease

https://en.wikipedia.org/wiki/Transcription_activator-like_e...


The main human genome is more than 6 orders of magnitude larger than the mitochondrial genome, if you measure by counting base pairs.


Edit the principal genes of the mitochondria (for example, increase the membrane's oxygen and CO₂ permeability) to make it extract more energy per unit time.


I don't think we know how to do that yet. But there's a big tradeoff mitochondria have to make in terms of either being more efficient at turning sugar into ATP or being more resistant to damage. Since most people in the first world have an easy time getting enough calories to survive it would make sense to lean into the resistance to damage side of things.


This has actually been achieved very recently:

https://www.nature.com/articles/d41586-020-02054-5


We can make IVF progeny with a separate mitochondrial parent, been doing that about a decade. We move ones we like between cells.


Mitochondria are really one of our cells' most under appreciated organelles and the consequences of them being "the powerhouse" are a lot more profound than you might think. I highly recommend Nick Lane's book on them, Power, Sex, Suicide: Mitochondria and the meaning of life, which explores the consequences of the biochemistry, population genetics, of mitochondria for how animals live in general. It's far more interesting than biochemistry has any right to be, along with his other books.


Yes and his book "The Vital Question", which covers some of the same ground. Highly recommend.


I agree. And thanks for that book recommendation. It is now on my list.


One day we will have a full biological understanding of anxiety and mental health, at which point people will no longer need to change the world around them.


There is a recent thread on how even CBT (Cognitive Behavioral Therapy) is akin to wire-heading[0], and we've known for ages that loneliness encourages depression and addiction[1] so it's not a far leap to suggest that adverse environmental conditions can be measurably, significantly even fatally unpleasant. I think this conclusion is also common knowledge, intuitively accessible to any observant adult. It's strange, then, that we spend so much time addressing the chemical conclusions at which individuals arrive by virtue of their social relations. I suspect there are political reasons behind the medicalization of depression. Why should my neurochemistry be held responsible for relations whose creature I socially remain?

0. https://twitter.com/buss_patriarchy/status/12890769568734658...

1. https://www.youtube.com/watch?v=C8AHODc6phg


It's so sad considering how we treat our mentally ill in the U.S.: we tell them to find a tent and a piece of sidewalk and look the other way when they walk up the street. How do you possibly heal from a mental health issue or addiction in an environment like that? How do you not just get worse and worse until something breaks?

You have no safety living on the street. None of your possessions are safe if you leave them alone. You have no money, no resources at all because any step forward to lift yourself out of this requires putting money down up front. People treat you less than human based on your appearance alone, which grows more haggard the longer you are living out there with few pairs of clothes and limited ways to wash them or yourself.

It's absolutely awful how we treat our mentally ill in this country, and the lack of any will to do anything about it from all levels of government.


Mental illness, like all illness, would benefit from universal, socialized medicine.

That's the "lack of any will to do anything about it from all levels of government" we should be worried about.


Knowledge that loneliness and environmental conditions impact depression is very much an incomplete picture. The causes of depression are far more complex and often recalcitrant to either life changes or medication.

Sure, if social conditions are the primary factor in a person's mental health problems then "blaming" and attempting to address the issue at a neurochemical basis with medication may not be warranted. But to paint the entire illness with that brush is to overlook the complexity of the problem.


That implies that all efforts to change external circumstances are linked to mental health issues.

Also understanding does not automatically lead to fixing. We understand a lot of things that we haven't been able to change. And what if the understanding we gain shows us that the causes of our anxiety and mental health issues are things in the world around us?


With anxiety borne from mental illness, at least in my experience, I cannot be sure if the anxiety I feel is more related to my internal state or external state. For instance, on a day when I am doing good, I eat a delicious meal, I am happy with it, on a day when I am doing bad, I eat a delicious meal I focus on the calories and my overall diet and my weight, etc.

In theory at least, with perfect mental health I will be able to confidently relate my feelings to the external world and be able to reason about changing the external world to deal with real anxieties rooted in perceptions of real danger.

I think for people who suffer from mental illness related to anxiety, or at least for me, the goal is not to completely eliminate anxiety but to be able to know that the anxiety I feel is reasonable and appropriate. (Similarly for my chronic depression)

Of course the line between reasonable and unreasonable anxiety is not always clear. The far points are clear, being anxious about some stranger approaching you with a gun, that's reasonable, being unable to get out of bed because you are certain everything is going to go wrong no matter what, that is unreasonable. But should you be anxious about this person because you did that thing but you have a history with this person and... that sort of thing is fuzzy.


Emotional trauma can trigger some serious mental illness. Some events change a personality forever.


A novel solution to the Fermi paradox


AHAHHHAA! I love this! being a Daoist and an old Buddhist, this understanding helped me so much with my OCD/Anxiety.


I don't understand the connection.


Although "all experience hath shewn that mankind are more disposed to suffer, while evils are sufferable, than to right themselves by abolishing the forms to which they are accustomed," organisms have been known to alter our environments to suit our needs, rather than suffer them even to our deaths. For example, when it rains I often open an umbrella.

Perhaps with the right anti-depressant cocktail, I wouldn't bother.


Based on what I've seen in nature films regarding how great apes (chimpanzees, orangutans, etc) react to rain, and the extreme aversion to being rained on that I've anecdotally seen in several different cultures, I have a suspicion that an aversion to rain--particularly to unwanted/unexpected rain--might be not only instinctual but peculiar and specific, similar to our aversions to spiders and snakes. Or maybe not, but it has definitely stood out to me.


If you don't need to change your environment (assuming mental health is the only reason to do so), why is it a problem that you won't have the inclination to do so?


The reasonable man adapts himself to the world; the unreasonable one persists in trying to adapt the world to himself. Therefore all progress depends on the unreasonable man.

George Bernard Shaw


Desire. Aversion. Desire. Aversion.


As explained by the nihilist Caterine Vauban (Isabelle Huppert ) to Albert (Jason Schwartzman) and Tommy (Mark Wahlberg) in I Heart Huckabees: "It is inevitable that you are drawn back into human drama: desire, suffering...." https://youtu.be/9EilqfAIudI?t=85 Pretty sure it's a riff on the traditional themes of Dharmic religions. (Not unique to them, though.)


It may be the case that the greater understanding will lead to a greater need for change.


Just take a couple grammes of soma and enjoy your vacation, fellow alpha plus!


Realizing mitochondria were the "powerhouse" due to a voltage gradient created by chemically transforming ATP to ADP across a membrane gave me a eureka moment about how small such a mechanism can be, and how powerful in great numbers.


the power house of the cell


What a durable educational meme. I think it shows the power of singularly concise descriptors when introducing a new subject. We need more of that.


> the power of singularly concise descriptors

Or the power of hackneyed sayings and satire :P


Exactly what I thought of when they said:

> “They’re the chief executive organelle of the cell.”

Which IMO sounds odd, given that Mitochondria are seldom described as having much "decision making" power.


Well, they do start the process of triggering apoptosis or cell suicide, for instance.


They are the Duracell of the cell.


I was hoping to see one of these. Thank you!


> In 1924, this man Boris Mikhaylovich Kozo-Polyansky wrote a book called Symbiogenesis: A New Principle of Evolution, in which he reconciled Darwin’s natural selection as the eliminator and symbiogenesis as the innovator.

TIL that evolution is a GAN.


Here is one of my favorite videos of mitochondrial transport, in vivo: https://www.youtube.com/watch?v=x5IxkI6tkn0

Apparently, there is a whole economy for transporting microchondria within dendrites. More mitochondria in an area of the dendrites allows for faster growth and responsiveness to input.

(There is another time-lapse video I've seen before of mitochondrial transport, but I'm frustrated that my own browsing history isn't making it easier to find. Are there tools that help make ones own browsing history more useful/accessible?)


Assuming the title is true, that'd make mitochondria the powerhouse of the self.


I wonder if there's a connection to Nicotinamide Riboside (NR) supplementation.

NR is a precursor to NAD+, which has been shown to improve mitochondrial function especially under stress.

NAD+ is one of those molecules used in a ton of metabolic processes and over a lifespan NAD+ avalability declines. This decline is linked to numerous age-related diseases. There's a bit of research showing NAD+ supplementation contributes to anti-aging effects.

NR is easy to take, well-tolerated, and a cheap precursor for NAD+. There are IV clinics that have NAD+ infusions, but they cost like $500. On the other hand, you can get a month's supply of NR for around $50 (Thorne's ResveraCel).


I recommend this book:

"Mitochondria and the Future of Medicine: The Key to Understanding Disease, Chronic Illness, Aging, and Life Itself"

-- by Lee Know

https://www.amazon.com/gp/product/1603587675


>Lee Know, ND, is a licensed naturopathic doctor based out of Canada, and the recipient of several awards. Known by his peers to be a strategic and forward-thinking entrepreneur and researcher, he has held positions as medical advisor, scientific evaluator, and director of research and development for major organizations. Besides managing Scientific Affairs for his own company, he also currently serves as a consultant to the natural-health-products and dietary-supplements industries, and serves on the editorial advisory board for Canada's most-read natural health magazine.

At least he's honest about his lack of medical expertise and conflict of interest.


And? Do you have any particular problems with any actual insights in the book? Do you think the medical industry is forward-thinking or adverse to new ways of thinking in general? I don't want this guy removing my appendix, but there are many cases of people outside or peripheral to a domain without qualifications that make a huge impact on a particular area and lead the way for more research -- and we are all aware of the medical establishment's lack of proper training when it comes to nutrition.


The problem I have is they're attempting to sound authoritative via way of medical and scientific expertise while in fact having none, in addition to having a financial interest in pushing supplements. It severely impugns the credibility of the book.

>Do you think the medical industry is forward-thinking or adverse to new ways of thinking in general?

Both. It's so vast that sweeping generalizations don't really apply.

>... but there are many cases of people outside or peripheral to a domain without qualifications that make a huge impact on a particular area and lead the way for more research ...

Sure, but an ND with ties to the supplement industry ain't that.

>... and we are all aware of the medical establishment's lack of proper training when it comes to nutrition.

You could even argue the medically-recommended low-fat diet craze was one of the largest health disasters in modern history. Unfortunately it doesn't make this guy any more correct or rigorous in his opinions.

Please understand this isn't a personal attack. I take supplements and aggressively fast every day precisely because I largely believe in the mitochondrial theory of aging. For all I know, everything in the book could be factually correct and not misconstrued. It doesn't change the fact the author is presenting themselves as a medical expert.


Whenever I see "X may hold keys to Y", I always augment it with "or it may not". In fact "may not" is the more likely outcome because if it did come anywhere close to "holding" the keys the headline would be affirmative.

It's a variant of Betteridge's law, if you will.


Ok Ray Peat


Hm, but I was told it’s only in my head!


Completely left-field comment:

> Carmen Sandi recalls the skepticism she faced at first. A behavioral neuroscientist at the Swiss Federal Institute of Technology in Lausanne, she had followed a hunch

I feel like people use “radical ideas” like this to justify whatever their bullshit of the day is, and generally ignore the fact that they almost always come from experts in their respective fields.




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