Ready. Aim. Fire: Mitochondria as Treatment Targets

The accumulating evidence that metabolic factors play a significant role in the many symptoms of mental disorders opens a whole new approach to treatment. Targeting mitochondrial function promises to add significantly to the effectiveness of current treatments for psychiatric disorders, if not replace them altogether. It also offers a possible way to prevent them in the first place.

For example, there are several everyday experiences known to impede mitochondrial function across the board; over time, their effects add up. Chief among them are poor quality and insufficient quantity of sleep. Getting good sleep is a wide-action strategy to renew mitochondria and their energy-producing capacity.

Poor diet is another lifestyle factor that takes its toll on mitochondria. After all, the mitochondria must make do with the nutrients we furnish them. Psychosocial stress is yet another everyday experience that directly affects the biological activity of mitochondria. Developing a rich array of coping skills and deploying well-tested stress-reduction measures such as expressive writing and meditation can mitigate the impact of distressing experiences on the brain and body.

In addition to limiting what undermines mitochondrial function, it’s possible to add measures that boost overall mitochondrial fitness. A healthy, produce-rich diet is one. Further, there are existing natural and synthetic compounds—curcumin, a polyphenol naturally found in turmeric, is one— that stimulate mitophagy, which removes damaged and aging mitochondria to maintain their metabolic capacity. Physical exercise is another readily accessible strategy for stimulating mitophagy; it activates mitochondrial quality control.

It is increasing possible for scientists to detect very specific malfunctions—including those due to genetic causes—in the many chemical interactions involved in metabolism. And to develop highly targeted workarounds. While such measures are not yet generally incorporated into everyday clinical psychiatry, they are on the way.

Sleep and Metabolism

Just as every organism does, mitochondria need their sleep. Sleep, researchers find, is “mitorestorative.” The high rate of mitochondrial activity during the day creates oxidative stress. Psychological stress—including the stress we experience as a result of sleep deprivation—compounds oxidative stress. Antioxidant defenses suffer. Lipid peroxidation increases, setting the stage for disease by damaging cell membranes.

Sleep is essential for protecting against oxidative stress, which gets corrected during sleep as mitochondria reshape to rebalance themselves. Studies show that sleep deprivation diminishes the bioenergetic capacity of mitochondria, decreasing the capacity to produce ATP.

Mitochondria don’t just need sleep—they seem to be the reason why we sleep. Studies show they are essential to regulating the circadian clock that governs the sleep-wake cycle. While they are destructive at high levels, at moderate levels, reactive oxygen species (ROS) serve as signaling molecules; researchers now believe that it is the buildup of mitochondrial ROS that specifically promotes sleep. Contemporary research into mitochondria suggests that the answer to the enduring mystery of why we sleep is to mitigate oxidative stress in the brain and restore the functional capacity of mitochondria.

Eating Well

The food we eat supplies the fuel that mitochondria burn for energy and an array of bioactive components essential for the process. Consuming a diet rich in fruits and vegetables, which also happen to be rich in fiber (something notoriously deficient in the standard American diet), has a broad effect on mitochondria: It delivers not only the carbohydrates to be broken down to glucose in mitochondria. It furnishes, among many other nutrients, a steady supply of antioxidants to defend against oxidative stress.

Among the nutrients known to protect mitochondria against oxidative damage are:

• Antioxidants—Abundant in fruits and vegetables, they directly neutralize reaction oxygen species, limiting oxidative stress.

• Omega-3 fatty acids—They maintain the fluidity of mitochondrial membranes and increase the efficiency of ATP production, curbing oxidative damage.

• B vitamins—Signaling molecules and cofactors for many of the chemical reactions in mitochondria, they modulate and maintain the efficiency of mitochondrial activity.

• Magnesium—The mineral boosts the efficiency of ATP production and reduces the production of reactive oxygen species, curtailing oxidative stress.

Ketogenic Diet

Ketogenic diets are nothing new. They have been used for a hundred years to reduce the frequency of brain seizures in infants and children with epilepsy. Low in carbohydrates, limited in protein, and high in fats, ketogenic diets force mitochondria to burn fats as fuel instead of glucose. The liver breaks down fats and sends them into the circulatory system in a form known as ketone bodies.

Supplying the brain with ketones as fuel, rather than glucose, increases the efficiency of ATP production. The increased availability of energy influences the levels of neurotransmitters to curb the hyperexcitability of neurons that leads to seizures. It also regulates calcium ions that control the firing ability of neurons. Studies show that ketogenic diets improve mitochondrial metabolism, neurotransmitter function, oxidative stress, and inflammation, while also increasing neural network stability and cognitive function.

Ketogenic diets also affect the microbiome, shifting the composition of bacterial species in a way that increases levels of GABA in the brain. Perhaps most important, ketogenic diets also stimulate mitophagy and mitochondrial biogenesis, leading to increased numbers of healthy mitochondria in cells.

Fasting

Fasting starves mitochondria. With no incoming fuel, the body turns to its fat stores as a source of energy—exactly what they are there for. Fasting resets the machinery of energy production, improving oxidative metabolism, curbing production of ROS and limiting oxidative stress, stimulating mitophagy and biogenesis. It also restores the sensitivity of insulin receptors, whose job it is to allow glucose into cells. Running on ketones, the brain gets a more efficient fuel source than glucose, and the increase in energy boosts cognitive performance. Fasting has also been shown to relieve the symptoms of depression and even stimulate complete remission in people with major depressive disorder.

Rejuvenating as fasting can be biologically, it is hard to do for very long. For the past few decades, researchers have been searching for ways to mimic its effects. Enter so-called fasting-mimicking diets, all of which prescribe periodic starvation—at varying intervals of time —to beef up metabolism in the brain.

Some fasting-mimicking regimens restrict food intake to 8, 10, or 12 hours daily; others alternate days of fasting with days of normal eating. A hot area of research, studies show such diets revitalize glucose metabolism and signaling pathways, activate mitochondrial housekeeping, and improve cognitive function even in those with mild dementia. Fasting-mimicking diets are being studied both as prevention and treatment of Alzheimer’s disease.

Nutraceuticals

Many compounds derived from foods have pharmacologic effects on tissue above and beyond their nutrient value. Such substances are often referred to as nutraceuticals. Many such substances participate in the chemical sequences of energy production, and a proper supply of them may both prevent and treat mitochondrial malfunction. A number of such compounds are extracted from foods and made available as supplements. Some studies have shown they can be effective in treating such disorders as depression both in major depressive disorder and in bipolar disorder. Their use and effects are still very much under investigation.

Among such substances:

NAC, or N-acetylcysteine—an antioxidant.

Co-enzyme Q10—another antioxidant.

L-carnitine— an amino-acid derivative that is an essential co-factor in energy production.

S-AME, or S-adenosyl methionine—a co-factor for many enzymes used in mitochondria including for regulating DNA and RNA transcription.

Physical Activity

Physical activity is essential for maintaining the health of most organs of the body, and it is a powerful non-pharmacological strategy for protecting mitochondrial health. Studies show that exercise regulates mitochondrial quality control mechanisms by which damaged mitochondria are repaired and recycled or eliminated (mitophagy), and it stimulates the synthesis of new mitochondria (biogenesis). Both processes are important for meeting the energy demands of brain cells and maintaining brain function. Physical activity also affects the shape of mitochondria, abetting processes of fusion that boost their energy-making capacity.

Many experts consider regular physical activity of moderate intensity the most powerful non-pharmacological way of maintaining mitochondrial function. It is as important for the health of the brain as it is for the heart.

Social Connection

Human beings are inherently social animals. What that means is that every facet of our biology and psychology is attuned to social interaction. And our minds and bodies suffer in its absence. Differences in sociability and social status among individuals are actually reflected in variations in mitochondrial shape and functional capacity in specific regions and circuits of the brain.

Social behavior both influences mitochondrial function and dynamics and is regulated by them. For example, mitochondria appear to be involved in the reduced sociability seen in such conditions as anxiety, depression, and autism, in part by controlling energy available to neurons in specific neurotransmitter circuits. In autism, mitochondrial hyperactivity affecting GABA levels is implicated.

Researchers know that early-life stress can lastingly alter mitochondria, reprograming many aspects of their activity and function —including energy availability and neurotransmitter release —essential to social behavior. Social and other stresses in adulthood also have multiple effects on mitochondria, such as increases in the production of reactive oxygen species, laying the groundwork for many kinds of physiological insults, including alterations in lipid metabolism.

Many nutrients from the foods we consume are required for proper mitochondrial activity. Boosting various aspects of mitochondrial function through nutritional intervention in animals has yielded a positive effect on sociability and has mitigated not only stress-induced social deficits but anxiety-like behavior and despair.

Targeting mitochondrial function in humans through drug and nutritional means may be a promising approach to remedying various types of social dysfunction undermining human health.