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Mitochondrial housekeeping

Mitochondria are the central source of ATP (adenosine 5′-triphosphate), the universal fuel for our body. ATP is generated through a process called oxidative phosphorylation, or OXPHOS.

Mitochondria wear out or get damaged by environmental factors, such as reactive oxygen species. Besides, mitochondria's function declines with age.

Mitochondrial housekeeping, also called mitochondrial hemostasis, ensures that a healthy pool of mitochondria is available to provide each cell with the required energy.

Every cell needs to keep a functional pool of healthy mitochondria through mitochondrial housekeeping. The accumulation of dysfunctional mitochondria is associated with metabolic and neurodegenerative disorders.

Mitochondrial housekeeping is regulated through a delicate balance between removal of damaged mitochondria and replacing these with new ones through mitochondrial biogenesis. Both mechanisms, the removal, and biogenesis of mitochondria are tightly regulated through genetic activities in the cell.

The primary genes involved in mitochondrial biogenesis are called peroxisome proliferator-activated receptor gamma (PARP-gamma), its co-activator PGC-1, nuclear respiratory factor-1 (Nrf-1) and 2 (Nrf-2) and the mitochondrial transcription factor A (Tfam).

A process called autophagy, which breaks down unwanted cellular components, is responsible for the removal of damaged mitochondria. In autophagy, the unwanted element is first surrounded by an envelope consisting of a double layer membrane, the autophagosome, that is then tagged to be transported and eliminated in lysosomes. The lysosomes are membrane-enclosed organelles and contain various enzymes that break down anything that is delivered to them. In principle, lysosomes are the garbage disposal units of the cells.

Mitophagy is a selective form of autophagy and is the primary mechanisms for the selective elimination of damaged mitochondria or parts of the mitochondrial network through lysosomal degradation.

What triggers mitophagy, how does the cell know that individual mitochondria are healthy while others are damaged?

The crucial elements to recognize damaged mitochondria are still not very well known. One hypothesis is that damaged mitochondria release from their inside, called matrix, a protein that sits on their membrane and tags the mitochondria as damaged. Other proteins, such as PINK1, Parkin and LC3-interacting protein recognize this tag and attract the envelope to wrap around the damaged mitochondria and transport it to the lysosome, concluding mitophagy.

Mitophagy does not only remove whole damaged mitochondria but parts of them, too. Debris generated in mitochondria is collected in a specific “corner” of the mitochondria, and this section of the organelle is tied off. It works in principle like a garbage bag; once the container is full, it is tied off and disposed of through mitophagy. This helps to remove garbage from otherwise healthy mitochondria without destroying the whole organelle.

The process that ties off the garbage bag section of the mitochondria is called mitochondrial fission.

Proper housekeeping and removal and replacement of damaged mitochondria with healthy ones is crucial for cellular function and bodies health in general.

Many diseases originate from dysfunctional mitochondrial hemostasis, or they disrupt housekeeping processes.

In either case, failure to remove damaged cells and garbage results reduces the number of healthy mitochondria in the cells, affecting its metabolism and energy generation.

Neurons have a high demand for energy and are very sensitive to fluctuations in its availability. Prolonged periods of energy starvation can cause neuronal degeneration.

Parkinson's Disease is thought to originate in defective mitochondrial housekeeping through the faulty regulation of the protein called Parkin and results in loss of dopaminergic neurons in the substantia nigra.

Alzheimer's Disease is a progressive disease that starts at early ages and becomes symptomatic in the elderly. Scientists have strong evidence that Alzheimer's Disease disrupts mitochondrial housekeeping through mitophagy and fission, and severely disables mitochondrial biogenesis.

In Huntington's Disease, an inherited neurodegenerative disorder, a genetic mutation results in highly dysfunctional mitochondria in cells producing the neurotransmitter GABA. The mitochondria in cells suffering from this Disease are highly fragmented and their ability to provide energy to OXPHOS severely disabled, resulting in the death of neurons.

In Amyotrophic lateral sclerosis or ALS, neuronal death starts later in life and becomes very fast symptomatic. Scientists have evidence that a genetic abnormality results in unwanted interference of the protein TDP-43 in OXPHOS and disable mitochondrial energy generation. Besides, mitochondrial housekeeping in ALS is also negatively affected by a so far unknown mechanism.

Now it is undeniable that mitochondrial housekeeping is crucial for mitochondrial health, specifically in neurons that rely upon and require a fully functional pool of healthy mitochondria. Neuronal health is directly correlated to mitochondrial health as is a car's performance requires a good engine.

But in contrast to car engines, and contrary to rumors created by so-called brain “experts” on the internet impersonating professional neuroscientist and brain doctors, so far there is no direct intervention possible to target specifically mitochondrial health.

Such an intervention would alter a very finely tuned mitochondrial balance and probably modify exact mechanisms that are responsible for mitochondrial hemostasis.

Tens of thousands of scientists work daily to understand mitochondrial hemostasis and health and are currently at the beginning of a long journey. Therefore, it is improbable that non-professional pseudo-neuroscientists have a safe way to directly promote mitochondrial health through dubious, in most cases illegal substances they peddle on the internet through social media for unlimited brain health, delayed brain aging, longevity, and superhuman mental powers.

No current scientific evidence supports these claims.

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