Mitochondria: A Unifying Link for Psychiatric Illness

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The evidence is amassing that alterations in brain energy metabolism are the first cause of all psychiatric disorders, from anxiety to schizophrenia, autism to Alzheimer’s disease. The metabolic theory of mental illness holds that all mental disorders are metabolic disorders of the brain, based in the mitochondria of neurons and other brain cells.

This isn’t just a shift in thinking about how disorders originate; it augurs a shift in doing, in using metabolic strategies to treat mental illness. Many such treatments are, in fact, already available and well-researched. Many more are in the works, as mitochondria become a target for the development of a new generation of drugs to treat psychiatric disorders.

As the generators of metabolism, mitochondria are the unifying link for all known risk factors of mental disturbance, whether genes, neurotransmitters, hormones, stress, adverse childhood experiences, rejection, or loneliness. That is because mitochondria are sensors of the environment—internal and external—and quick to react to changes in it.

In the past few years, as researchers have begun measuring such factors, more and more preclinical and clinical studies have reported abnormalities in brain energy metabolism, electron activity, and genes associated with mitochondrial functions in stress-related disorders, anxiety, depression, bipolar, schizophrenia, and autism spectrum disorders. Genetic studies are also pointing to mitochondrial mutations in mental illnesses.

The Mitochondrial View of Stress

The mitochondria are what connect mind and body, translating social and psychological experiences into emotional responses—positive and negative—and clinically meaningful biological and physiological changes. Stress is a mental state of challenge. It consumes energy. It is metabolically taxing. It especially alters the activity of mitochondria in the cortex and striatum, brain structures involved in many behavioral processes associated with anxiety.

Just as mitochondria produce the energy required for life, they generate the signals that enable adaptation to stress. Chronic stress alters multiple elements of mitochondrial biology. Changes in mitochondria are thought to be a key way that adversity gets embedded in biology, setting the stage for the development of disease.

In turn, variations in mitochondrial energy production capacity alter social behavior, stress reactivity, and mood. Numerous studies link negative mood and negative life experiences to diminished capacity of the mitochondrial energy machinery.

Stress is not the only disposition to affect mitochondrial function. In at least one study, researchers have found that the experience of happiness one day boosts the energy-producing capacity of mitochondria the next day. Mitochondria play a key role in health as well as disease.

Trauma and Mitochondria

Researchers have evidence that early life trauma, such as severe or multiple adverse childhood experiences (ACEs), can reprogram mitochondrial energetics. For example, they have detected higher levels of mitochondrial DNA mutations in adult women with major depression who had experienced parental loss or maltreatment in childhood, compared to women without depression. Early damage to mitochondrial DNA through traumatic experiences can lastingly alter various molecules that are part of the mitochondrial energy-making machinery and signaling cascades.

Anxiety

There appears to be a mitochondrial signature of anxiety. Looking at such classic anxiety behaviors as threat vigilance and social avoidance, both of which are responses to stress, researchers find that the behaviors are linked to mitochondrial energy production activity in specific areas of the cortex and striatum. The same two areas have earlier been linked with anxiety behaviors in imaging studies of neural circuitry patterns.

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The adage that neural circuits that fire together wire together can now be expanded: They also respire together, exhibiting similar variations of energy activity.

Depression and Suicide

Brain imaging studies, many done to establish the neural circuitry of depression (indicating which brain areas play a role in the disorder), have long shown abnormalities in metabolic activity in the brain structures found to be involved, implicating abnormal energy metabolism. Some areas are metabolically overactive, some underactive. In addition, it is well-established that depression heightens the risk for, and often occurs along with, metabolic diseases such as obesity, diabetes, metabolic syndrome, and cardiac disorders.

Mitochondria are especially important for neural plasticity, long known to be compromised in depression. They are also important regulators of calcium, essential to neurotransmission. Studies of mitochondria in depression and other mood disorders show impairments in energy production along with increased levels of oxidative stress. The findings highlight the role of boosting antioxidant defenses to neutralize reactive oxygen species (ROS) as a possible treatment strategy for depression, alone or in combination with drug treatment.

Mitochondrial dysfunction plays a role not just in depression but also in suicide. Researchers examining the blood of men and women with treatment-resistant depression and suicidal ideation have identified specific molecules that distinguish suicidal thinking—all of them known to be involved in mitochondrial energy production. Inside mitochondria, the biochemicals are part of ATP synthesis, but outside the cell, abnormal levels of the biochemicals signal mitochondrial dysfunction.

The researchers suggest that “suicide attempts may actually be part of a larger physiological impulse to stop a stress response that has become unbearable at the cellular level.” Monitoring mitochondrial function by measuring blood levels of mitochondrial metabolites may have clinical value as a predictor of suicide risk.

Bipolar Disorder

Many signs of mitochondria malfunction are detected in various studies of bipolar disorder, from brain imaging to blood analysis, to post-mortem examination of brain tissue. Findings include diminished levels of ATP, misshapen or undersized mitochondria, unusual distribution of mitochondria in neurons, abnormal amounts of various mitochondrial metabolites, irregularities in electron mechanics, abnormal triggering of cell death in specific brain areas, increase in ROS production, and more.

Mitochondrial dysfunction can lead to abnormal levels of calcium ions (regulated by mitochondria) at synapses, creating the hyperexcitability of neurons that underlies mania. Mitochondria are now major targets for the development of new treatments for the disorder.

Schizophrenia

Known genetic risk factors for schizophrenia may work by impairing mitochondrial function in various ways. One way is by failing to produce proteins that help mitochondria to move about the cell. Mitochondria normally are highly flexible and very mobile, changing shape and zipping around the host cell to where they are most needed at the moment, dividing and fusing to meet energy demands. Proper neuron development especially requires mitochondria to be in the right place at the right time. Problems with mitochondrial dynamics are particularly implicated in schizophrenia, along with other disruptions of mitochondrial function, including lack of enzymes essential in the energy-production process.

Autism

Mitochondrial dysfunction is present in the vast majority of children and adults with autism. Given their vulnerability to damage, mitochondria may be affected by many types of insults—from environmental toxins to shortage of key vitamins and minerals to excessive stress—during the developmental process, when the need for energy is particularly great. The multiple sources of mitochondrial damage along with the variety of cell processes potentially affected may help explain the wide array of symptoms associated with autism spectrum disorder.

Addiction

Substances of abuse such as alcohol, cocaine, and methamphetamine impair tissue health and produce their behavioral effects by targeting mitochondria. Among other things, they hamper the ability of mitochondria to gather at synapses when their energy is needed most, disrupting neurotransmission in areas of the brain such as the hippocampus and in dopaminergic neurons.

Cocaine affects mitochondrial function in a number of ways—altering electron transport, production of reactive oxygen species and oxidative stress, mitochondrial dynamics, and mitophagy. Researchers believe that developing treatments that maintain the functional integrity of mitochondria may help mitigate the damage of drugs of abuse.

Dementia

For decades, researchers have been focused on accumulations of beta-amyloid and tau proteins in the brain cells of people with Alzheimer’s disease, as well as on neuroinflammation and brain atrophy, as the cause of cognitive deterioration. But treatments targeting these processes have all notably failed, likely because they are late consequences of more basic pathologic changes.

More recent evidence suggests that mitochondrial dysfunction—especially impaired mitophagy—is a more primary change, occurring well before the traditional hallmarks of Alzheimer’s, and plays a major role in development of the disease. Molecules that stimulate mitophagy are currently in various stages of development and testing as treatment for the disorder.