The Mitochondrial Hegemony

 

Mitochondrial Hegemony

More on a mitocentric view of life.

A recent publication ¹ has shown that in the development of Parkinson’s Disease (PK), mitochondria switch to a situation where their substrate or ‘feedstock’ is from fatty acids rather than from  normal metabolism of glucose. 

This may sound esoterically biochemical and just a specific example from a particular disease, but it is of great significance. To me, it is another example of mitochondria ‘deciding’ the fate of cells. But this last sentence requires elucidation because it has been well known for many years that cell death, surely the ultimate example of a cell’s fate,  is initiated by mitochondria. 

Specifically, cell death is started by electrical depolarization of mitochondria followed by a release of the weakly-bound protein Cytochrome C from the inner mitochondrial membrane through the outer membrane which in turn sets off a cascade of reactions leading to cell death.

So what is significant about the first example which is observed in Parkinson’s disease?

What I want to posit is another shift in the 50yr scientific  journey of mitochondria from a mere structure, an organelle so called,  which is specialised in chemical energy transduction thence to modern orthodoxy (where it is now a symbiont) derived from free-living bacterial-like origins and living in subordinate partnership with its nucleated host cell. 

The next shift is to see the mitochondrion in a much more powerful role. A role which puts mitochondria at the very centre of life. Simply put, the mitochondria are ‘in charge’ of the cell not vice-versa. The mitochondria are living in a cellular ecosystem which they are able to reproduce into large trillion-cell organisms. 

 

A few supporting facts

Mitochondria provide the free-energy to maintain the low-entropy situation of a multicellular organism.

Multicellular undifferentiated clumps are possible without mitochondria². Typically as an example cancer-tumours have disabled their mitochondria (to prevent them initiating the cell death switch) but without the vast amounts of energy supplied by mitochondria the structure of the tumour is almost non existent and supplies of nutrients and disposing of waste prevents any viability outside host-victim.

Mitochondria have a fully functioning genome³

Few mitochondrial genes reside in the bacteria-like circular DNA within the mitochondria itself. What is there is highly redundant ( many gene copies ) which is unsurprising as mitochondria are in effect free-radical furnaces and gene damage highly likely. Most mitochondrial genes are to be found now in the relative safety of the host cell’s nucleus where it is tended and repaired but more importantly it is communicated with via a process called retrograde signalling. In other words mitochondria have outsourced their genetic information: stored it in the ‘cloud’ to use a modern analogy.

Mitochondrial energy-transduction biochemistry is ‘kludged*’ with its host’s energy -transduction biochemistry

The title above needs a fair amount of unpicking to make sense but can be appreciated maybe through an imaginative narrative well described nowadays and beautifully fleshed out in Wikipedia⁴:

Imagine free-living mitochondria emerging in a world that is becoming oxygen-rich as a result of photosynthetic activity. Imagine also vast pools of oil-like hydrocarbons resulting from decaying photosynthetic organisms. 

Mitochondria  fully oxidise a chemical we call acetyl. Essentially, acetyl consists of two carbon, three hydrogen and one oxygen atom. 

In my imaginary scene mitochondria are getting acetyl from free fatty acids (oily stuff) basically by chopping off two carbons at a time and hydrating them ( adding water) using a very complicated enzyme complex found on their inner membrane. They can still do this today and is coincidently described in the first paragraph of this essay.

Now imagine a bacteria-sized mitochondrion having been engulfed by a primitive, hunting amoebic-like cell … finding itself in paradise and being fed abundant acetyl, gratis! 

This is exactly what happens today. The ancient biochemistry we call glycolysis essentially takes sugars whose basic unit comprises six carbons and breaks them down to two, two-carbon units releasing a modest amount of free energy. Acetyl units for free.

The imaginary host cell above uses glycolysis to partly metabolise sugars without oxygen and the captured mitochondrion laps it up. Free food is rapidly fully oxidised to carbon dioxide and water and a powerhouse chimera is born. Over and over again and at some point the chimera persists and multiplies.

But, back to the title of this section, we have two alien biochemistries which are getting along fine but still have a long way to achieve glitch-free integration. My contention is that millions of years later with thousands of evolutionary modifications the junction between the two biochemistry has all the hallmarks of a kludge and should be seen as such and we often feel its effects even today.

 

To sumarise. What is this chimera? Is it a partnership of equals? Does one party dominate the other? Are ‘we-multicells’  just ‘Matrix-like’ hosts to the dominance of the mitochondria?

From a Dawkins’ selfish-gene perspective, for genes it is a win-win whatever your origin and as such a pointless distinction is being made. But from a physiological-health and longevity of organisms, ie ‘us’ the relationship between mitochondria and host does matter. 

Examples, just three of many relationships that matter:

For:  in the Parkinson’s example at the start of this article why has the junction failed, why have the mitochondria reverted to fat metabolism? 

Or; when we age we get fat disproportionately from sugar consumption as mitochondria fail to metabolise the acetyls and they are stored as fat

Or finally, during viral infection  whether oncogenic or simply a pathogen like Covid 19, mitochondria are in the front line destroying cells before they themselves are switched off.

By adopting a mitocentric view of life we may begin to see connections and causes overlooked in the past.

*kludge: an ill-assorted collection of parts assembled to fulfil a particular purpose.

1.    https://www.ebi.ac.uk/metabolights/MTBLS2266/descriptors

2.    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950268/#:~:text=Mitochondrial%20dysfunction%20induced%20by%20somatic,might%20contribute%20to%20cancer%20progression.

3.    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468901/#:~:text='%20Mitochondrial%20retrograde%20signalling%20is%20a,survival%2C%20drug%20resistance%20and%20metastasis.

4.    https://en.wikipedia.org/wiki/Symbiogenesis

5.    Biosystems. 2013 Jan; 111(1): 1–10.

 

Post script August 2024

During a person's lifetime, evidence has emerged that mitochondria insert their DNA in small blocks into the cell's nuclear DNA. This occurence has been discoverd in post mortem studies on the pre-frontal cortex of human brains. The insertions occur multiple times over a lifetime but occured more often in cadarvers that died at a younger age ... and vice versa.

No mechanism for early death has been put forward. But in the context of this article it is fun to speculate that the mitochondria 'sense' something in their cellular world is amiss, likely affecting their own health and are attempting to put something right.

Malfunctioning mitochondria will generate more free radicles and may hasten cell death as a result. What are the mitochondria signalling and why?

https://www.cuimc.columbia.edu/news/mitochondria-are-flinging-their-dna-our-brain-cells#:~:text=Their%20analysis%20showed%20that%20nuclear,than%20individuals%20with%20fewer%20NUMTs.