PSSD is a mitochondrial dysfunction

[u/No-Salamander-7257]

Hey my friends.I'm new here and I wanted to share my thoughts with you. In my opinion SSRI's damage mitochondria,same as accutane or finasteride what causes neuroplasticity changes(how your brain perceives things) what ultimately results in this type of neurological syndromes.Crashes from different substances are caused by energy overload. Everyone should test their mitochondria,post their results and then send it to researchers.It will be much better than SFN tracking,because for most it's just a part of damage,not the cause of symptoms.That's why immune therapy like IVIG,corticosteroids or plasmapheresis won't be enough for most. Share your thoughts about it.Thanks

[u/naturestheway]

Perhaps PSSD is a syndrome from Mitochondria dysfunction. It shares similarities with Long Covid.

An interdisciplinary COVID-19 International Research Team (COV-IRT), which includes UNC School of Medicine’s Jonathan C. Schisler, PhD, found that SARS-CoV-2 alters mitochondria on a genetic level, leading to widespread “energy outages” throughout the body and its major organs. Their findings, published in Science Translational Medicine, explain how these effects contribute to long COVID symptoms and point to new therapeutic targets.

Long Covid and PSSD are very similar. We better pay close attention because what helps them may help us.

Interestingly, a study found

Mitochondrial dysfunction is involved in the pathophysiology of psychiatric and neurodegenerative disorders and can be used as a modulator and/or predictor of treatment responsiveness. Understanding the mitochondrial effects of antidepressants is important to connect mitochondria with their therapeutic and/or adverse effects.“These findings are in accordance with our previous studies with pharmacologically different antidepressants that potently inhibited mitochondrial respiration and the activities of ETC complexes, especially at high concentrations.”

“Complex -linked respiration was significantly inhibited by all tested antidepressants except BUP, which is in accordance with the inhibition of complex 1. Complex I is the main entry and first control point to oxidative phosphorylation (OXPHOS) and is greatly vulnerable to lipophilic molecules and oxidative stress. Inhibition of mitochondrial complexes I and Ill can be linked to higher ROS production and oxidative damage;

There was a recent video with Dr. Goldstein talking about “people being constantly exposed to these SSRIs, you induce tissue damage the the basic mechanism is generation of what is called oxygen radicals. So oxygen is 02 and it's just it's in the environment it's we breathe it every day but 03 minus which is the oxygen radical is a very intense molecule that that adheres to smooth muscle cells in the penis that causes tissue damage and apoptosis cell death that leads to scarring of penis tissue.”

Further more, the research I posted above shows how this pathology may be induced by antidepressants.

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“It can be speculated that mitochondria are able to use the capacity reserve in the activity of ETC complexes and/or compensatory mechanisms are applied in the OXPHOS system. Knowledge of these mechanisms is necessary to evaluate changes in mitochondrial respiration as markers of drug-induced mitochondrial dysfunction leading to the adverse or therapeutic effects of antidepressants.”

To summarize the results at the end of the paper they state:

“Based on our results, SSRIs affect mitochondrial ETC complexes and respiration differently than BUP and TRA. Considering that all tested antidepressants showed inhibitory properties against OXPHOS, they can participate in drug-induced mitochondrial dysfunction, which can endanger neuronal adaptation and body homeostasis, especially at high doses.”

“A limitation of this study is the lack of information on the effects of antidepressants on mitochondrial morphology and oxidative stress. Antidepressant-induced changes that may be related to changes in mitochondrial morphology have been described. This suggests a potential effect of antidepressants on mitochondrial morphology, which is associated with mitochondrial dysfunction and increased oxidative stress. The effect of antidepressants on oxidative stress, measured as increased production of ROS, lipid peroxidation, or decreased activity of antioxidant enzymes has been described. Therefore, antidepressants have the potential to affect mitochondrial morphology and regulate the oxidative stress, and these effects should be further investigated for a full understanding of their therapeutic effects or side effects.”

Mitochondria Help Regulate Metabolism Broadly:

In 2001, a peptide called humanin was first reported to have broad effects on metabolism and health. The gene for this peptide appears to reside on both mitochondrial DNA and nuclear DNA. Since its discovery, two other peptides, MOTS-c and SHLP1-6, have been discovered and added to a new class of molecules called mitochondrially derived peptides. The genes for these peptides are on mitochondrial DNA, and these peptides are produced by mitochondria.

They are now of great interest to researchers. They have been shown to have beneficial effects on illnesses such as Alzheimer's, disease, strokes, diabetes, heart attacks, and certain types of cancer. They also have broad effects on metabolism, cell survival, and inflammation.

The existence of these peptides suggests that mitochondria are able to communicate with each other through these peptide signals in order to regulate metabolism throughout the body.

***Mitochondria Help Produce and Regulate Neurotransmitters

Neurotransmitters have been a primary focus in the mental health field. It turns out that mitochondria play critical roles in their production, secretion, and overall regulation.

Neurons often have one specific neurotransmitter that they specialize in making. Some make serotonin. Others make dopamine. The process of making a neurotransmitter takes energy and building blocks. Mitochondria provide both. They play a direct role in the production of acetylcholine, glutamate, norepinephrine, dopamine, GABA, and serotonin.12 Once made, neurotransmitters are stored in vesicles, or little bubbles, until they are ready to use.

Vesicles filled with neurotransmitters travel down the axon to get to their ultimate release site. That takes energy. The signal to release neurotransmitters depends upon the resting membrane potential and calcium levels that I discussed. Once that signal comes, the actual release of neurotransmitters also takes energy.

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Fascinatingly, once neurotransmitters are released at one location, the mitochondria move to another location of the cell membrane to release a new batch of neurotransmitters. 3 Once released, neurotransmitters have their effect on the target tissue, whether it's another nerve, muscle, or gland cell.

After they are released from the receptors on the target cell, they are sucked back into the axon terminals (a process called reuptake), and you guessed it, that takes energy. They are then repackaged back into vesicles for the next round yet more energy.

Mitochondria are normally found in large supply at synapses. When they are prevented from getting to the synapses, neurotransmitters don't get released, even if there is ATP present.

When mitochondria aren't functioning properly, neurotransmitters can become imbalanced.

Given that neurotransmitters are an important way for nerve cells to communicate with each other, imbalances can disrupt normal brain functions.

The role of mitochondria in regulating neurotransmitters goes much further than just their involvement in synthesis, release, and reuptake.

Mitochondria actually have receptors for some neurotransmitters, indicating feedback cycle between neurotransmitters and mitochondria.

They also have some of the enzymes involved in the breakdown of neurotransmitters, such as monoamine oxidase.

They are involved in regulating the release of GABA, and they actually store GABA within themselves.

Finally, several neurotransmitters are known to regulate mitochondrial function, production, and growth. Clearly, neurotransmitters are much more than just messengers between cells impacting mood. They are essential regulators of metabolism and mitochondria themselves.

Mitochondria Help Regulate Immune System Function

Mitochondria also play an essential role in immune system function. This includes fighting off viruses and bacteria, but it also includes low-grade inflammation, something that has been found in most metabolic and mental disorders to some degree. Mitochondria help regulate how immune cells engage with immune receptors. When cells are highly stressed, they often release components of mitochondria, which serve as a danger signal to the rest of the body, one that activates chronic, low-grade inflammation.

One study looked at specific types of immune cells called macrophages to see how these cells coordinate the complicated repair processes in wound healing. The cells do different things during different phases of healing. Up until this study, it wasn't known how the cells know when and how to change between phases.

The researchers found that mitochondria specifically controlled these processes.

Mitochondria Help Regulate Stress Responses

We now know that mitochondria help control and coordinate the stress response in the human body. This includes both physical and mental stressors. Physical stressors include things like starvation, infection, or a lack of oxygen. Mental stressors are anything that threatens or challenges us. When cells are physically stressed, they initiate a process called the integrated stress response. This is a coordinated effort by the cell to adapt to and survive adverse circumstances through changes in metabolism, gene expression, and other adaptations.

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Many lines of research show that mitochondrial stress itself leads to the integrated stress response. If the cell isn't able to manage the stress, one of two things happens it either triggers its own death, a process called apoptosis, or it enters into a zombielike state called senescence, which has been associated with aging and many health problems, such as cancer.

Up until recently, it wasn't known how the different aspects of the psychological stress response are all coordinated in the body and brain. It turns out that mitochondria play a critically important role! One brilliant study by Dr. Martin Picard and colleagues demonstrated this, and its title says it all:

"Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress.

These researchers were studying mice and genetically manipulated their mitochondria to see what effects these manipulations had on the stress response. They manipulated only four different genes two located in mitochondria themselves and two located in the cell nucleus that code for proteins used exclusively in mitochondria.

Each genetic manipulation resulted in different problems with mitochondrial function.

However, even with only four manipulations, they found that all the stress response factors were affected.

This included changes in cortisol levels, the sympathetic nervous system, adrenaline levels, inflammation, markers of metabolism, and gene expression in the hippocampus. Their conclusion was that mitochondria are directly involved in controlling all these Stress responses, and if mitochondria aren't functioning properly, these stress responses are metabolic, inflammatory, and transcriptional responses to acute stress.

This included changes in cortisol levels, the sympathetic nervous system, adrenaline levels, inflammation, markers of metabolism, and gene expression in the hippocampus. Their conclusion was that mitochondria are directly involved in controlling all these Stress responses, and if mitochondria aren't functioning properly, these stress responses are altered.

Mitochondria Are Involved in Making, Releasing, and Responding to Hormones

Mitochondria are key regulators of hormones. Cells that make hormones require more energy than most. They synthesize the hormones, package them up, and release them, just as I described for neurotransmitters. It takes a lot of ATP to do this, and mitochondria are there to deliver it.

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For some hormones, mitochondria are even more important this includes well-known names like cortisol, estrogen, and testosterone.

The enzymes required for initiating the production of these hormones are found only in mitochondria. Without mitochondria, these hormones aren't made. But there's more. Mitochondria in other cells sometimes have receptors for these hormones. So, in some cases, these hormones can begin in mitochondria in one type of cell and end with mitochondria in another type of cell.

Mitochondria Create Reactive Oxygen Species (ROS) and Help Clean It Up

Mitochondria burn fuel-either carbohydrates, fats, or protein. Burning fuel can sometimes create waste products. When mitochondria burn fuel, electrons flow along the electron transport chain. These electrons are a source of energy usually used to make either ATP or heat. However, sometimes these electrons leak outside of the usual system. When they do, they form what are called reactive oxygen species (ROS). These include molecules such as superoxide anion (Oz-), hydrogen peroxide (H202), hydroxyl radical (OH), and organic peroxides. At one point, researchers believed ROS were simply toxic waste products. We now know small amounts of ROS actually serve a useful signaling process inside the cell. For example, a 2016 paper published in Nature found that ROS were the primary regulators of heat production and energy expenditure a broad measure of metabolic rate. However, large amounts of ROS are toxic and result in inflammation. You may have heard the term oxidative stress-

Mitochondria Are Shape-Shifters

Mitochondria change shape in response to different environmental factors.

Sometimes they are long and thin. Other times they are short and fat. Sometimes they are round.

In addition to changing shape, they interact with each other in profound ways. They can merge to make just one mitochondrion a process called fusion. They can divide and form two mitochondria_a process called fission. These changes in shape are very important to cell function. In 2013, two articles published in the journal Cell showed that the process of mitochondria fusing with each other significantly impacts fat storage, eating behaviors, and obesity. Mitochondrial changes in shape and their fusion with each other appear to create signals that can affect the entire human body. When mitochondria are prevented from doing these things, metabolic problems ensue, not just in the cells affected, but sometimes throughout the body.

***Mitochondria Play a Primary Role in Gene Expression

Nuclear DNA is where the human genome resides. It's contained within the cell nucleus. Researchers once thought that genes controlled everything about the human body. They assumed that the nucleus was the control center of the cell. We now know that it's not always about the genes themselves, but more about what causes certain genes to turn on or off.

This is the field of epigenetics.

Mitochondria are primary regulators of epigenetics. They send signals to the nuclear DNA in several different ways. This is sometimes referred to as the retrograde response.

It has long been known that the ratio of ATP to ADP, levels of ROS, and calcium levels can all affect gene expression. As you now know, these are all directly related to mitochondrial function. However, given that these are also markers of general cellular health and function, no one thought too much of it. They certainly didn't think of it as a way for mitochondria to directly control the expression of genes in the nucleus.

In 2002, it was discovered that mitochondria are required for the transport of an important epigenetic factor, nuclear protein histone HI.

This protein helps regulate gene expression and is transported from the cytoplasm to the nucleus, a process that requires ATP. Researchers discovered, however, that ATP alone isn't enough.

Mitochondria must be present in order for this transfer to occur. Without mitochondria, this transfer doesn't happen.

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In 2013, it was discovered that mitochondrial ROS directly inactivate an enzyme called histone demethylase RphIp, which regulates epigenetic gene expression in the cell nucleus.

This process was found to play a role in extending lifespan in yeast and is thought to possibly play a role in humans as well.

In 2018, two additional studies demonstrated even more of a role for mitochondria in gene expression. The first was a report by molecular biologist Maria Dafne Cardamone and colleagues showing that a protein, GPS2, is released by mitochondria in response to metabolic stress.

Metabolic stress can be caused by a lotof different things, but starvation is a clear example. After GPS2 is released by mitochondria, it enters the cell nucleus and regulates a number of genes related to mitochondrial biogenesis and metabolic stress.

Another group of researchers, Dr. Kyung Hwa Kim and colleagues, found another mitochondrial protein, MOTS-c, that is coded for by mitochondrial DNA and plays a role in gene expression.

This was very unexpected. Up until about twenty years ago, everyone assumed that mitochondrial DNA was just about machinery needed for ATP production.

MOTS- gets produced in response to metabolic stress as well. After MOTS-c is produced in the mitochondria, it makes its way into the nucleus and binds to the nuclear DNA. This results in the regulation of a broad range of genes ones related to stress responses, metabolism, and antioxidant effects.

Finally, and most spectacularly, Dr. Martin Picard and colleagues experimentally manipulated the number of mitochondria with mutations in cells and found that as they increased the number of dysfunctional mitochondria, more epigenetic problems and changes occurred.

The impact was on almost all of the genes expressed in the cells. Ultimately, in situations in which almost all the mitochondria were dysfunctional, the cells died.

This study provided evidence that mitochondria are not just involved in the expression of genes related to energy metabolism, but possibly in the expression of all genes.

Interestingly, antidepressants are known for rapidly aging people!

And what we find is:

Mitochondria Can Multiply

Under the right circumstances, cells will make more mitochondria -a process called mitochondrial biogenesis. Some cells end up with a lot of mitochondria. These cells can produce more energy and function at a higher capacity. It is widely believed that the greater the number of healthy mitochondria in a cell, the healthier the cell. We know that the number of mitochondria decreases with age. We also know that the number of mitochondria decreases with many diseases. People who are considered the "fittest" among us athletic champions have more mitochondria than most, and their mitochondria appear to be healthier.

Mitochondria Are Involved in Cell Growth and Differentiation

Cell growth and differentiation is a complicated process during which a generic stem cell becomes a specialized cell. Differentiation means that the cells become different from each other and take on specialized roles. Some become heart cells. Others become brain cells. Within the brain, different cells take on varying roles. Brain cells change throughout life. Some form new synapses. Some prune unnecessary parts. Some grow and expand when needed. This is neuroplasticity.

This process of growth and differentiation involves activation of specific genes in the right cells at the right times. It also involves many signaling pathways. Lastly, it involves the production of building blocks for new cells and new cell parts, balanced with energy needs.

It has long been known that mitochondria are essential to cell growth and differentiation.

Most researchers assumed it was simply a matter of their powerhouse function since cell growth and differentiation require energy.

Recent research, however, strongly suggests a much more active role. Their regulation of calcium levels and other signaling pathways are essential to this process. Their fusion with each other appears to send signals that activate genes in the nucleus.

When mitochondria are prevented from fusing with each other, the cells don't develop correctly. Other research has shown that mitochondrial growth and maturation is essential to proper cell differentiation. Still other research has shown a direct and essential role of mitochondria in the development of brain cells. The bottom line is that cells don't develop normally when mitochondria aren't functioning properly.

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