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February 4 - April 8, 2025
Autophagy and apoptosis are somewhat related, but they are different processes. Autophagy is usually about repairing and replacing parts within a cell, but the cell usually remains alive. Apoptosis is the death of an entire cell. Nonetheless, they are both required for health and longevity, and mitochondria play a role in both.
Over the past twenty years, a lot of the new evidence on the role of mitochondria in the cell has been shocking and unexpected. Almost no one thought that mitochondria could control the regulation of genes in the nucleus—both on a daily basis and during cell growth and differentiation. Their interaction with and regulation of other organelles, such as the endoplasmic reticulum and lysosomes, were also surprising. They were usually thought of as relatively insignificant, and very small, ATP factories. They were sometimes described as “little batteries.”
mitochondria are the only organelles that move around the cell, interact with each other, and interact with all the other organelles. Mitochondria were in the cell first. They were the first organelle. They were also an independent living organism at one point.
one thing is abundantly clear and uncontroversial—when mitochondria aren’t working, neither is the human body or brain.
In the 1980s, it was discovered that infusing lactate into the vein of a person with panic disorder would often precipitate an immediate panic attack.
The specific psychiatric disorders in which mitochondrial dysfunction has been identified include the following: schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism, anxiety disorders, obsessive-compulsive disorder, posttraumatic stress disorder, attention deficit/hyperactivity disorder, anorexia nervosa, alcohol use disorder (aka alcoholism), marijuana use disorder, opioid use disorder, and borderline personality disorder.
Dementia and delirium, often thought of as neurological illnesses, are also included.
In 1954, Dr. Denham Harman proposed the free radical theory of aging, which focused on ROS as the cause of age-related diseases. In 1972, he further developed this theory and proposed the mitochondrial theory of aging, which recognized the central role of mitochondria in the production of ROS.
Wallace argued that the brain is the organ that will be most affected by a problem with energy production by mitochondria.
So, a small amount of energy deprivation might result in ADHD or depression and a larger amount of energy deprivation might result in other disorders, such as schizophrenia.
What these researchers failed to consider is how many other roles mitochondria play in cells apart from the production of energy. They also failed to recognize just how many different factors affect the function and health of mitochondria. When mitochondria don’t function properly, neither does the brain.
Mitochondria are producing ROS, and if they produce too much of it, it can damage the mitochondrial DNA or other parts. This can lead to defective mitochondria. When mitochondria are defective, they are supposed to be disposed of and recycled, with new ones taking their place. If this doesn’t happen, a cell can be left with a workforce shortage. It’s well established that the number of mitochondria in our cells decreases as we get older, resulting in less metabolic capacity for cells.
As the mitochondria continue to decline, the cell usually dies. This leads to organs and tissues shrinking. As the cells die off, the organs get weaker and more vulnerable to stress. Brains shrink. People lose muscle mass. The heart isn’t as strong. This phenomenon is also seen in people with chronic mental disorders.
mitochondrial dysregulation. Many of the factors that affect mitochondrial function come from outside the cell. They include neurotransmitters, hormones, peptides, inflammatory signals, and even something like alcohol.
Even though most people think of obesity as a surplus of energy, many cells in the bodies and brains of people with obesity are actually deprived of ATP, due to mitochondrial dysfunction.7
oxidative stress. Remember, this is a term used to describe the buildup of ROS.
Numerous studies have found higher levels of oxidative stress in essentially all of the metabolic, neurological, and mental disorders that I have been discussing. This has been linked to cell damage and accelerated aging.
Focus on just one function. Most studies have focused on only one function or aspect of mitochondria.
Some cells can have perfectly healthy mitochondria in abundance, while other cells can have defective or insufficient mitochondria. Researchers must study specific cells to determine whether mitochondria in those cells are playing a role in an illness.
We know the more beta-amyloid that is present, the more likely it is that someone will develop Alzheimer’s disease. We also know it is toxic to mitochondria and causes mitochondrial dysfunction.8 Many researchers have stopped there. They feel they have enough evidence that mitochondria are innocent bystanders of this destructive protein. What causes beta-amyloid to accumulate? They don’t know.
mitochondrial dysfunction might very well be the cause of the accumulation of beta-amyloid itself.
One study estimates about one-third of the brain’s ATP production goes to cell maintenance or “housekeeping” functions.
They also interact with the endoplasmic reticulum (ER), which has many roles including the folding of proteins. Many neurodegenerative disorders are associated with misfolded proteins in the ER.
there is a microprotein on the outer membrane of mitochondria, PIGBOS, that plays a key role in the UPR. When this protein was eliminated, the cells were much more likely to die.
structural defects in cells can lead to a positive feedback cycle that affects metabolism and can make it harder for cells to work.
Myelin makes it easier for neurons to send electrical signals. If a neuron has defects in its myelin coating, it will require more energy to work. An extreme example of this is multiple sclerosis, in which myelin is destroyed by an autoimmune process. Mitochondrial dysfunction has been associated with problems in myelin production and maintenance. Consistent with the brain energy theory, defects in myelin have been identified in the brains of people with schizophrenia, major depression, bipolar disorder, alcoholism, epilepsy, Alzheimer’s disease, diabetes, and even obesity.13
Debris in the cell, another structural defect and maintenance issue, can impair mitochondria from moving around.
this is probably the most paradoxical thing about mitochondrial dysfunction. Sometimes when mitochondria aren’t working properly, parts of the brain can actually become overactive as opposed to underactive—even though they may not have enough ATP.
mitochondria are involved in ion pumping and calcium regulation, which are both required to turn cells “off.” If mitochondria aren’t functioning properly, these processes will take longer to perform, and cells can become hyperexcitable.
dysfunction in cells that are meant to slow down other cells, such as GABA cells. If GABA cells aren’t working properly, then the cells they are supposed to inhibit will become unleashed and hyperexcitable.
These maintenance problems can cause hyperexcitability; for example, a lack of myelin can allow ions to leak into a cell and cause it to fire when it shouldn’t.
mitochondrial dysfunction causes hyperexcitability by deleting a protein in mice, sirtuin 3, known to be essential to mitochondrial health. Sure enough, the mice developed mitochondrial dysfunction, hyperexcitability, and seizures, and they died early deaths.
Hyperexcitability has also been found in the brains of people with delirium, PTSD, schizophrenia, bipolar disorder, autism, obsessive-compulsive disorder, and Alzheimer’s disease. It has even been measured in healthy rodents subjected to nothing more than chronic stress.
Reduced cell function alone explains many of the altered levels of neurotransmitters and hormones seen in people with mental disorders. Additionally, mitochondria are directly involved in making some of the hormones, such as cortisol, estrogen, and testosterone, so if they are dysfunctional or dysregulated, these hormone levels may be dysregulated, too.
Mitochondrial dysfunction can lead to cell shrinkage, or atrophy. If the quantity or health of mitochondria declines, the cell gets stressed.
In some cases, mitochondria stop going to peripheral parts of the cell, such as axon terminals or dendrites. When they stop going there, those cell parts die. Inflammation ensues.
the brains of people with chronic mental disorders show signs of cell shrinkage over time.
hippocampus, are more commonly impacted, but even in people with the same diagnosis, such as schizophrenia, there can be numerous differences in the brain regions impacted.
timing and development also matter. People who are affected at age fourteen will have brain differences from people not affected until thirty-nine.
people with depression have lower levels of ATP, not only in brain cells, but also in muscle cells and circulating immune cells.
levels of oxidative stress are elevated in people with depression.
The biomarkers related primarily to amino acid and lipid metabolism, both of which relate to mitochondrial function.
biomarker of great interest is acetyl-L-carnitine (ALC).
lower levels of ALC predicted the severity of depression, the chronicity of the illness, treatment resistance, and even a history of emotional neglect.
nucleus accumbens, to see if there were differences in mitochondrial function and/or how the cells developed. They found both. The anxious/depressed rats had fewer mitochondria per cell, as well as differences in the way their mitochondria used oxygen to turn energy into ATP and in how mitochondria interacted with another organelle, the endoplasmic reticulum (ER). The neurons themselves also looked different. Following the trail further, the researchers found that the mitochondria from these rats had lower levels of mitofusin-2 (MFN2), a protein on mitochondrial membranes important to their
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Changes in sleep, energy, motivation, and concentration likely all relate to reduced function of brain cells.
There are many studies documenting mitochondrial dysfunction in bipolar disorder, with findings similar to those found in people with depression.
manic states appear to be one of the few unique situations in which mitochondria, at least in some brain cells, are producing more energy than normal.
Bipolar patients have been found to have higher than normal calcium levels, especially when they are manic—consistent with the hyperexcitability mechanism that I outlined.
One group of researchers recently identified a mitochondrial biomarker in blood cells showing a significant decrease in the number of mitochondria in both manic and depressed states that normalized when people were feeling well.29 This suggests that something might be disrupting either mitochondrial biogenesis or mitophagy throughout the entire body during disease states, not just in the brain.
