Mitochondrial Dysfunction in Psychiatric Illness

According to the endosymbiotic theory, mitochondria were once free-living bacteria that were engulfed by another cell over a billion years ago, creating the original eukaryotic cells. Over time, they transferred much of their genetic material to the nucleus but retained their own mitochondrial DNA as well.¹ This symbiotic relationship with mitochondria allows us as eukaryotes and humans to generate energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation, which is carried out by the mitochondrial electron transport chain.¹ The electron transport chain is a series of 5 enzyme complexes that are located on the inner mitochondrial membrane. During oxidative phosphorylation, reduced cofactors generated from the oxidation of nutrients such as glucose donate electrons to complex I and complex II. Electrons are then passed from complex to complex, down an electrochemical gradient. The flow of electrons is coupled to the pumping of protons from the mitochondrial matrix into the intermembrane space, and this proton gradient is then used to drive the production of ATP.

Reactive oxygen species (ROS) are generated as by-products of oxidative phosphorylation. ROS can cause oxidative damage to mitochondrial and cellular proteins, lipids, and nucleic acids and have been implicated in a number of diseases as well as aging. Mitochondria are also the site of other key cellular metabolic processes such as the beta-oxidation of fatty acids, the urea cycle, and the Kreb’s cycle.¹ In addition, mitochondria are critical to cellular homeostasis and are involved in apoptosis, calcium regulation, and intracellular signaling.¹

Although mitochondria were traditionally depicted as discrete cigar-shaped structures, it has become apparent that in fact they form dynamic networks as a result of a frequent fission and fusion event.² Mitochondria are also dynamic and move in the cytoplasm along microtubule tracks, assisted by molecular motors.²

As the main energy producers of the cell, mitochondria are critical to all body systems and particularly critical to highly energy-dependent organs such as the brain. Impairments in mitochondrial function have been associated with many neurological disorders,³ and there is now a convincing body of evidence implicating mitochondrial dysfunction in psychiatric illness.

In this issue of the journal, 2 articles review the literature on mitochondrial function and psychiatric disorders. The first article by Bergman and Ben-Shachar⁴ focuses on mitochondria and oxidative phosphorylation in schizophrenia. They review the many cellular processes that may be influenced by oxidative phosphorylation, including calcium buffering, cell signaling, ROS production, and apoptosis. They review evidence suggesting that in schizophrenia, there are significant mitochondrial deficits that are limited in magnitude and propose that these deficits may result in abnormal brain development, synaptic plasticity, and network connectivity that are observed in patients with schizophrenia. In the second article, Machado et al.⁵ review the literature implicating mitochondrial dysfunction in bipolar disorder and other psychotic disorders. They outline a number of “upstream” factors that control mitochondrial function and how ROS may affect signaling pathways and myelination, as well as cause DNA and RNA damage in bipolar disorder.

The wealth of data included in these 2 reviews demonstrates the robust evidence for mitochondrial dysfunction in both schizophrenia and bipolar disorder. The exact mechanisms and pathways by which mitochondria contribute to the pathophysiology of mental illness remain to be fully elucidated. In some patients, genetic mitochondrial DNA mutations may directly cause neuropsychiatric symptoms, but this is likely to represent a minority of psychiatric patients.⁶ It is more likely that mitochondrial DNA single-nucleotide polymorphisms (SNPs) and SNPs in nuclear DNA encoding mitochondrial proteins may contribute to the risk of developing psychiatric disorders in some patients. In addition, alterations in ROS, mitochondrial dynamics and trafficking, calcium homeostasis, and cellular signaling pathways as a result of mitochondrial dysfunction may lead to the clinical manifestations of mental illness. Further research to understand these different pathways and delineate how they differ in schizophrenia, bipolar disorder, and other psychiatric disorders will be important. This could potentially lead to novel therapeutic targets. For example, N-acetylcysteine (NAC) modulates oxidative stress, apoptosis, mitochondrial function, and neurogenesis, and emerging evidence suggests NAC may be effective in a number of psychiatric disorders.⁷ Understanding the role of mitochondrial function in psychiatric disorders may also lead to a better understanding of the therapeutic effects and side effects of current psychotropics, particularly antipsychotics that directly impair mitochondrial function. This could lead to strategies that might mitigate some side effects and improve our current therapies for patients with mental illness.