How an archaic collusion between bacteria and archaea gave rise to mitochondria, eukaryotes, sex and keto diet

Where do you get your energy? From mitochondria.

@MetaphysicalCells

“Everything in the world is about sex, except sex. Sex is about power.”

Oscar Wilde

According to our best scientists earth was formed around ~4.5 billion years ago — being at the time just a piece of rock slammed by meteorites and tormented by erupting volcanoes — and for the first 2 billion years all creatures alive on this rock were single cells with no nucleus. 

Then something strange happened. An unexplained mystery back then.

Surprisingly and out of nowhere, the single-celled microorganisms archaea — similar to bacteria but evolutionarily distinct from bacteria — were invaded by the bacteria alpha-proteobacterium.

Now, just before the invasion these innocent archaea were just living happily ever after around volcanic ridges on the ocean floor of young earth, and they were fed on CO2 and H2. While the alpha-proteobacteriuma were living in the vicinity and were fed on organic compounds, discharging as waste products CO2 and H2 that the archaea made use of. 

But then, like any military action consisting of armed forces where one geopolitical entity is entering the territory controlled by another entity, the bacteria attacked the archaea conquering their territory.

After tolerating the bacteria for a while — and not protesting against this military hegemony and plenty of arrogance of the alpha-proteobacterium — however, the invaded archaea evolved (became smarter) to take advantage of bacteria and ended up integrating them for good.

So, the bacteria became the mitochondria, namely the powerhouses (producing energy) of their hosts archaea. A useful symbiosis, after all, is the best thing for everyone.

But then something absolutely remarkable happened, that changed the history of earth and paved the way for all complex life forms.

Thanks to these new powerhouses (the archaic mitochondria), the archaea had plenty of energy ready for use and so they afforded to build a kind of new control centre, like a new government — the cell “nucleus” — and evolved from archaebacteria (organisms made of one cell with no nucleus) into eukaryotes — organisms made of one or more cells with a nucleus, like us. 

At the end, what started as an arrogant invasion by the bacteria, allowed to the archaea to start a new “civilisation” on earth, that is the famous and well known “eukaryotic mega-kingdom (actually a domain)” that conquered the earth eventually, and created the four kingdoms of Protista, Fungi, Plantae and Animalia.

Fast forward that very important prehistoric event of power demonstration, and today most of our DNA (~20,000 genes) sits in the nucleus of each of our cells (~30 trillion cells). Outside the nucleus, however, our mitochondria have retained some DNA of their own: a circular genome known as the mitochondrial DNA (mtDNA). 

Initially of course the mtDNA was bigger, but since the mitochondria generate a lot of free radicals (waste) by being the powerhouses of the cells, probably much of the genetic material of the archaic mitochondria ended up in their host cell’s nucleus, to be better protected from the free radicals produced by the same mitochondria (Being right on Q: shaping eukaryotic evolution).

In particular, the mitochondria as powerhouses they produce adenosine triphosphate (ATP) — the primary carrier of energy in cells — and heat from digested food with the help of the 02 we inhale. In this process, they dump as waste products C02 (that we exhale), H20 (that we pee out) and free radicals. Most of these free radicals are coming from oxygen atoms and are called Reactive Oxygen Species (ROS).

Because of the continuous exposure of the mtDNA to ROS and due to the absence of protective histones in the mtDNA — namely the proteins that protect the DNA against hydroxyl radical-induced DNA strand breaks — scientists now believe that

• during evolution most of the genes of the alpha-proteobacterium abandoned their initial mtDNA-base to settle down in a more friendly place (histone rich) in the nucleus. And

• since the mtDNA has a higher mutation rate (being histone free) than the nuclear DNA, that creates in the end a level of somatic mosaicism (mitochondrial heteroplasmy).

In other words, as a result of the ROS the mtDNA has been reduced during evolution through gene transfer to the nucleus. So, nowadays, mammalian mtDNA encodes only 13 of the ~1,500 proteins of the mitochondria proteome, accordingly the mitochondria depend on the nucleus for most of their proteins and lipids (The Mitochondrial Proteome and Human Disease).

However as the mutations tend to accumulate in these few mtDNA genes, this can give rise to mitochondrial heteroplasmy, the coexistence of different mtDNA variants within a single cell, whose levels can vary considerably between cells and organs. 

The subsequent accumulation of these deleterious variants — during development and aging — is the cause of severe progressive mitochondrial disorders that play a major role in many conditions, including aging, cancer, diabetes and neurodegenerative disorders like Alzheimer’s or Parkinson’s disease (Mitochondrial heteroplasmy beyond the oocyte bottleneck).

For example, mitochondrial genetics studies in animals have indicated that mitochondrial function impacts brain function and behaviour. In particular, when mice were generated to contain an equal mixture of two different types of mtDNA (heteroplasmy), their neurons got confused. Given that this mixture of otherwise normal mtDNAs had undetectable consequences on energy production, it was striking to observe that these heteroplasmic mice exhibited impaired memory retention capacity. 

Thus, subtle changes in mitochondrial bioenergetics can have broad effects on mammalian brain function: Heteroplasmy of mouse mtDNA is genetically unstable and results in altered behavior and cognition.

But (hopefully), even though most mtDNA genes tend to accumulate mutations  — so by the time people reach reproductive age their mitochondria are quite on the pathway leading to corrosion — yet these mitochondria and their genes do not appear to be passed to the next generation in this damaged state.

In fact, eukaryotic cells are very intelligent.

As a matter of fact, the egg cells (ovum or female gametes) carry solely fresh, unspoiled “template mitochondria” that they keep in storage and start using them only after their fertilisation.

In particular, the female gametes in the ovaries usually spend their days doing almost nothing — just sitting all day and enjoying their life like in a deep meditative state — and the little energy they need they can get it from much less efficient sources than mitochondria or from the mitochondria of nearby cells in the ovary.

After all, for all the women who’ve been called lazy, NO you are not lazy, you are smart safeguarding your mitochondria. 

On the other hand, the sperm cells (male gametes) they can’t afford to be lazy doing nothing. Evolution had other plants for them: they have only “one mission impossible” in their life, and that is to win a swimming race. For that reason, they are forced to "exploit" their own mitochondria to produce as much as possible the energy they need to win their race. Yes exploit them…, even with the cost of destroying them from the ROS produced in the process.

And this is actually the reason why exclusively maternal inheritance of mitochondria may have arisen. 

In fact, eukaryotic parents mix only their genes but don't mix their mitochondria, because for mitochondria men are just about dead ends, and their future makes no difference to mitochondrial future. After all, no one wants overworked, overstressed male mitochondria.

But mitochondria are also connected with sex. 

In point of fact, many scientists agree that the evolution of sex is likely to have a lot to do with mitochondria. Yes, you thought you had sex for pleasure, but your mitochondria might be more important.

Nick Lane, a British biochemist and writer, suggested in his book (Life ascending: the ten great inventions of evolution) that the early mitochondrion would provide an unending source of foreign DNA that would have contaminated the nuclear genome, and this contamination of foreign DNA would have imposed selection for recombination (namely sex) between host genotypes to preserve nuclear chromosomes with beneficial mutations, while purging deleterious ones. This view is supported by evidence that introns (non-coding regions of an RNA transcript, or the DNA encoding it, that are eliminated by splicing before translation) in the nuclear genome are of mitochondrial origin!

Furthermore, Damian K. Dowling and his colleagues also hypothesised that the mutational dynamics of the mitochondrial genome would have favoured the evolution of sexual reproduction. Since mtDNA exhibits a high mutation rate across most eukaryote taxa, that suggests that this high rate is an ancestral character, but what seems inexplicable is that the mtDNA-encoded genes underlie the expression of life’s most salient functions: energy conversion. 

Probably, according to these scientists this negative metabolic effect linked to mitochondrial mutation accumulation would have invoked selection for sexual recombination between divergent host nuclear genomes in early eukaryote lineages.

Under this hypothesis, recombination (sex) provides the genetic variation necessary for compensatory nuclear coadaptation to keep pace with mitochondrial mutation accumulation: The evolution of sex: A new hypothesis based on mitochondrial mutational erosion.

After all, who would have said that the tiny arrogant alpha-proteobacterium would have started a sexual revolution by invading the archaea billions of years ago!

At the end of the day sex is indeed power, mitochondrial power! 

Anyway, leaving behind us “Science for Adults” let’s go back again to “Mitochondrial Science”.

Another interesting fact about mtDNA is that the closest relatives of many mtDNA-modifying enzymes, such as mtDNA polymerases (involved in DNA replication and repair), are bacteriophage proteins. This suggests that an infection of the mitochondrial ancestor contributed to the development of the mtDNA maintenance machinery. 

That in plain English means, that after the alpha-proteobacterium attacked the archaea in a classical move of imperialism and colonialism (and power games…), subsequently a bacteriophage (a virus that infects bacteria) attacked the alpha-proteobacterium transferring also its genetic material (think of a USB transferring files to PC)…(First and foremost, the greatest power is not money power (or energy power), but political power. - Walter Annenberg)

That, in the end makes eucaryotes a trilateral agreement of cooperation between an archaea, a bacteria and a phage.

Another thing you should know is that the number of copies of mtDNA is not the same for everyone, though, and this is not an easy number to interpret. A smaller number should stand for reduced mitochondrial efficiency, and on such grounds reduced efficiency of body and brain (Our Mother’s Mitochondria and Our Mind).

For example, among healthy elderly women, those who do worse in a cognitive abilities' test have fewer copies than those who do better, and those who are depressed have fewer copies than those who are not.

But, if these tiny powerhouses are so important how can we protect them? In other words, “What If I Could Turn Back Time” for mitochondria and protect them from aging?

Well, with the right diet this might be possible.

Believe it or not, today we know that the ketogenic diet increases the number of mitochondria in our brain cells. 

For example, a recent animal study found enhanced expression of genes encoding for mitochondrial enzymes and energy metabolism in the hippocampus, a part of the brain important for learning and memory, after a keto diet: A cDNA microarray analysis of gene expression profiles in rat hippocampus following a ketogenic diet.

Keep in mind that hippocampal cells often degenerate in age-related brain diseases, leading to cognitive dysfunction and memory loss.

The ketogenic diet — which is high in fat and low in carbohydrates — mimics the metabolic state of starvation, forcing the body to utilise fat as its primary source of energy. Usually, the mitochondria generate ATP (energy trapped and stored in high-energy phosphate bonds) via oxidative phosphorylation, mainly by using pyruvate derived from glycolytic processing of glucose. 

To put it another way, normally human bodies are sugar-driven machines that they ingest carbohydrates and break then down into glucose. The glucose is then used for generating ATP (tiny blocks of energy) or it is stored as glycogen in the liver and muscle tissue.

But when we are deprived of dietary carbohydrates (usually glucose below 50g/day), the ketone bodies generated by fatty acid oxidation can serve as alternative metabolites for ATP energy production. Put in a nutshell, when the liver glycogen is depleted — because carbs have been eliminated or minimised — a backup mechanism consisting of ketone bodies (hydroxybutyrate, acetoacetate and acetone) that the liver derives primarily from fatty acids in our diet or body fat are released into the bloodstream, taken up by the brain and other organs, shuttled into the “energy factory” mitochondria and used up as fuel.

Notably, a keto diet may inhibit a major source of neuronal stress and mitochondrial stress, such as the ROS the unfortunate byproducts of cellular metabolism.

In particular, ketones directly inhibit the production of these violent molecules:

• by enhancing their breakdown through increasing the activity of glutathione peroxidase, a part of our innate anti-oxidant system. By doing so they just protect our mitochondria and brain: Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity. And

• by enhancing NADH oxidation in the mitochondrial respiratory chain. NADH is a crucial coenzyme in making ATP: KETONES INHIBIT MITOCHONDRIAL PRODUCTION OF REACTIVE OXYGEN SPECIES PRODUCTION FOLLOWING GLUTAMATE EXCITOTOXICITY BY INCREASING NADH OXIDATION.

Finally, the ketone bodies are also regulating gene expression (through NF-κB) by targeting specifically the gene responsible for the production of the Brain-derived neurotrophic factor (BDNF), related to the canonical nerve growth factor, improving neuronal bioenergetics and enhancing neuroprotection.

To tell the truth, this diet is so efficient, that has a long history of success in treating epilepsy in children and a multitude of other neurological and non-neurological conditions including autism, Alzheimer’s and Parkinson’s disease, traumatic brain injury and stroke.

To wrap it up, to make your mitochondria happy and safe in order to produce more energy, just eat well, meditate more like the female gametes and have good sex.

And remember, that the next time a phage (technically a bacteria virus) infects for some reason your cells, chances are that your mitochondria (technically bacteria) might start a new gene transfer to the nucleus, hopefully, pushing forward this time the biggest revolution of love on planet earth.

Thank you for reading 💙