Mitochondria Are More Than Powerhouses–They're the Motherboard of the Cell

I feel like the field of metabolic psychiatry is a very promising one. I can say from personal experience that switching to a ketogenic diet along with regular monitoring my blood ketone levels has had a huge impact on my ADHD related doldrums. Over the past two years it has helped me with the motivation and drive to lose weight, consistently exercise, and made it easier to create new habits which seem to have stuck. It seems strange that simply (although radically) altering your diet can lead to a life changing virtuous circle, but that's been my experience.

Learning biology is a great insight to how humans think about complex systems. We tend to utilize a reductionist and engineering approach to figure out how things work. This is a perfectly valid approach when building up a complex system from knowable individual parts.

But when analyzing a complex biological system, we tend to make analogies to our own engineered components (motherboards, power sources, circuits). There are definitely a lot of similarities and it is a great way to understand one facet of the system. But it can also sometimes make us lose sight of the intertwining relationships among all of these parts through evolution.

The analogy of our genome to an informational blueprint is one of the best examples of the multi-faceted nature of biology. While the sequence of bases contained within DNA (primary structure) is informational, the complex structures the molecule itself (chromatin structure) also have mechanistic purposes.

We build engineered components to be controllable and independent so we can better assess how the system is working. However, that is not an explicit goal with biology. Biological "components" settle into the best form for the given environment over time even if it creates a potential "mess" of connections and relationships.

I think this is also why biology takes a long time to "sink in" while learning compared to other technical fields. It's very easy to over-train your mental biological model on one facet of the system and lose sight of the others.

It is not uncommon to see the same terminology used in very different ways in various sub-fields of biology. Gene Ontology is also a great example of this as people have found there are biases associated with what the originator lab is studying at the time. Genes with pleiotropic function will tend to get assigned function that's more relevant to what the lab is interested in.

Sometimes I wonder if we are really equipped to navigate it and understand it. Maybe AI/computation is really the only way to try to have a holistic view of the complexities. Perhaps trying to understand biology with our biological brain has inherent limitations like a piece of software trying to understand the hardware it resides in.

This metaphor may be misleading. For a compelling alternate view, read the excellent: "Is the cell really a machine?" https://www.sciencedirect.com/science/article/abs/pii/S00225...

From the article:

"It has become customary to conceptualize the living cell as an intricate piece of machinery, different to a man-made machine only in terms of its superior complexity ......"

" ..... However, the recent introduction of novel experimental techniques capable of tracking individual molecules within cells in real time is leading to the rapid accumulation of data that are inconsistent with an engineering view of the cell ...... which emphasizes the dynamic, self-organizing nature of its constitution, the fluidity and plasticity of its components, and the stochasticity and non-linearity of its underlying processes."

If you like Mitochondria stuff, This book about the Krebs cycle and how it was discovered is pretty good: https://nick-lane.net/books/transformer-the-deep-chemistry-o...

The short answer is: First you have to murder a pigeon to extract fresh breast muscle cells. Then you put those cells in a manometer which uses columns of water to measure respiration via tiny changes in gas volume. From there you can add various things like citric acid and see how that affects respiration.

So figuring out mitochondria required murdering a large number of pigeons. Their breast muscles have some of the highest rates of respiration known, many times better then ours.

Reading this book inspired me to attempt to improve my mitochondrial health. So far the only stuff that seems to make a difference is NAD+ and Creatine.

Eukaryogenesis is a fascinating topic, and "motherboard" doesn't do it justice.

For efficient respiration, you need to have the translation/transcription of certain ATP synthase genes near to the membrane for basically JIT-ing them when ready to maintain membrane potential, and hence energy generation. Otherwise, the membrane potential falls apart. This simple need is why there are zero multicellular bacteria and multicellularity evolved 6 times in eukaryotes.

By decoupling the rest of the genome from the JIT bits (ie, mitochondrial DNA), you can scale energy independently of genetic information. So if you need 1000x the energy, you need like 5% more DNA (mitochondrial DNA) instead of 1000x more DNA in your genome.

Some estimates say that our eukaryotic genes are in charge of 5000x more energy than the equivalent bacterial gene. Hence, our genomes can inflate that much and its fine. And they have. All that inflation lets us have bullshit hang around in our genome, and hey, sometimes evolution figures out something to do with all that bullshit. We evolved 1000x more complexity than bacteria because we decoupled the performance code from the rest of the code.

The story of mitochondria is one of input mismatches. You get no UV, yet are warm. You see blue light, yet it’s night time. It’s day time, yet there is no NIR. You eat CHO heavy meals in the winter, yet nothing would grow at that latitude with the limited UV yield.

I could go into everything that goes into redox status, non-visual opsins, leptin and melanin, pgc1a, DHA, lack of cofactors (esp minerals), deuterium, and the list goes on… but nothing matters. All you need is to respect nature, wear blue light blockers at night, go outside, expose yourself to the elements, move, eat what you would have access to given the current UV yield, and supplement with tryspike.store’s MB-0.1 (due to soil depletion).

Fascinating article. Learned a lot. Especially about Lynn Margulis. What a great scientist. And she married Carl Sagan to boot.

Here's the part I don't understand about Mitochondria.

- I have a love-hate relationship with alcohol. I love it, it hates me. Turns out that alcohol really messes with mitochondria. And could be blamed for the inflammation and obesity epidemic (via mitochondrial disregulation).

- But then I see pics of people at beaches and public squares in the 60's and 70's. They were drinking way more than we do now. And they look skinny as heck. (As heck!)

- And apparently, for hundreds (thousands?) of years in various parts of the world (especially the middle ages West, and ancient Egypt), people pretty much drank water mixed with alcohol all day (it was safer than raw water), and their food was a type of thick beer porridge.

- So it can't be all that simple now, can it?

This article reminds me of something my psychiatrist said: "cells are typically classified by the role they perform, but I think it's better to classify them based on the type of mitochondria they have." Especially as it talked about the different mitochondria in neurons.

Also there's recent research on cells exchanging mitochondria[1] which is pretty surprising.

1: https://www.nature.com/articles/d41586-025-01064-5

There is all this variety in their behavior, shape, and influence on our biology, yet they have only 37 genes? How many nuclear genes augment these 37 to make all of this possible? Do any of these genes encode for the ribosome proteins necessary to convert the remaining genes into proteins?

What guides the behavior of a mitochondrion utterly lacking mtDNA? I suppose they still contain the proteins these genes code for, so maybe the genes are needed only for repair and reproduction.

Fascinating.

This may be relevant- I was just reading another article about migratory bird mitochondrial transition when migrating or not.

https://www.quantamagazine.org/turbocharged-mitochondria-pow...

“Endosymbiosis” always seemed so …eukaryocentric.

There is a reason that longevists, longevity researchers, and biohackers focus on mitochondrial enhancement through various means, supplementing NAD/NR, Ubiquinol, PQQ, ALCAR, photobiomodulation, etc

"Your eyes transform light into electrical impulses that coalesce into an image in your visual field, and your ears transform air-pressure waves into electrical pulses that you eventually perceive as sounds. Likewise, mitochondria transform dozens of hormonal, metabolic, chemical, and other information streams into their electrical membrane potential. This “bioenergetic” state then leads to the production of secondary messenger molecules that are intelligible to the nucleus. So in the same way you read messages on your phone, which receives signals, transforms them and projects decipherable information onto its screen, the nucleus of your cells can “read” the environment through the MIPS that surrounds it. Rather than having supplementary roles like those of battery chargers, mitochondria are more like the motherboard of the cell. Genes sit inert in the nucleus until energy and the right message come along to turn some of them on and some others off. Mitochondria provide these messages, speaking the language of the epigenome—the malleable layer of regulation that sits on top of the genome to regulate its expression.

My colleague Timothy Shutt of the University of Calgary likes to call mitochondria the “CEO of the cell”: the chief executive organelle. This metaphor captures how mitochondria not only are involved in integrating information but also give orders. They dictate whether the cell divides, differentiates or dies. Indeed, mitochondria have a veto on cell life or death. If the MIPS deems it necessary, it triggers programmed cell death, or apoptosis—a form of self-sacrifice for the greater good of the organism.

So vital are mitochondria that in difficult times cells may donate entire mitochondria to other cells. “In cellular emergencies, newly arrived mitochondria might kick-start tissue repair, fire up the immune system or rescue distressed cells from death,” journalist Gemma Conroy noted in a Nature news story last April. Inside tumors, cancer cells and immune cells appear to compete for mitochondria, using them as a kind of bioweapon. An international effort I participated in, led by Jonathan R. Brestoff of the Washington University School of Medicine in St. Louis, recently created an entirely new lexicon to guide the emerging field of mitochondria transfer and transplantation. All well and good, you may think. What does all this mean for my health or how long I’m going to live?

The short answer is that it may have everything to do with human health. Diabetes, neurodegenerative conditions, cancer and even mental health illnesses are all emerging as metabolic disorders involving malfunctioning mitochondria. And these findings are indicating new routes for intervention.

Mitochondria drive health—or disease—in several ways. One route derives from their role as energy processors. In an electrical circuit, if we crank up the input voltage too much, we can blow it out. Similarly, if our cells are exposed to too much glucose or fat—or, worse, both together, causing what doctors refer to as glucolipotoxicity—the mitochondria undergo fission and fragment into little bits, accumulate mtDNA defects, and produce signals that end up prematurely aging or killing the cell. Experiments in cells and in mice have shown that pharmacologically or genetically preventing mitochondrial fission induced by excessive glucose and fats may protect against insulin resistance. Cancer, too, may be a disorder of cellular metabolism. Cancer cells can burn glucose without oxygen, which suggests either that something is wrong with their mitochondria or that they prefer to reserve mitochondria for use in cell division—and proliferation.

A second pathway is through mitochondria’s influence on gene expression. Mitochondrial signals alter the expression of more than 66 percent of genes in the nuclear chromosomes. By changing which genes are expressed and to what extent, mutations in mtDNA may completely alter the nature, behavior and stress resilience of cells and ultimately of the whole organism."

Ray Peat PhD (RIP) and Chris Palmer MD have both emphasized the role of bioenergetics in human functioning, especially brain functioning.

Metaphor taken way too far...

Who is the superIO chipset of the cell? Who are the VRMs?

In case of interest, maybe also see its related https://news.ycombinator.com/item?id=44052898

https://news.cnrs.fr/articles/a-map-of-energy-in-the-brain

Edit: I see that the other submission is marked as a "dupe": it is not - a shorter introduction to the article in Nature. The submission of this page is the narrative presentation from a main researcher.

Edit2: though of course if we wanted to consider a submission as "news" instead of "content", then the two submissions are related. Dang, maybe we could think of an HN feature where linked submissions are somehow grouped?