Mitochondrial Dysfunction and Psychiatric Disorders
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- Rezin, G.T., Amboni, G., Zugno, A.I. et al. Neurochem Res (2009) 34: 1021. doi:10.1007/s11064-008-9865-8
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Mitochondrial oxidative phosphorylation is the major ATP-producing pathway, which supplies more than 95% of the total energy requirement in the cells. Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of psychiatric disorders. Tissues with high energy demands, such as the brain, contain a large number of mitochondria, being therefore more susceptible to reduction of the aerobic metabolism. Mitochondrial dysfunction results from alterations in biochemical cascade and the damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neuropsychiatric disorders, such as bipolar disorder, depression and schizophrenia. Bipolar disorder is a prevalent psychiatric disorder characterized by alternating episodes of mania and depression. Recent studies have demonstrated that important enzymes involved in brain energy are altered in bipolar disorder patients and after amphetamine administration, an animal model of mania. Depressive disorders, including major depression, are serious and disabling. However, the exact pathophysiology of depression is not clearly understood. Several works have demonstrated that metabolism is impaired in some animal models of depression, induced by chronic stress, especially the activities of the complexes of mitochondrial respiratory chain. Schizophrenia is a devastating mental disorder characterized by disturbed thoughts and perception, alongside cognitive and emotional decline associated with a severe reduction in occupational and social functioning, and in coping abilities. Alterations of mitochondrial oxidative phosphorylation in schizophrenia have been reported in several brain regions and also in platelets. Abnormal mitochondrial morphology, size and density have all been reported in the brains of schizophrenic individuals. Considering that several studies link energy impairment to neuronal death, neurodegeneration and disease, this review article discusses energy impairment as a mechanism underlying the pathophysiology of some psychiatric disorders, like bipolar disorder, depression and schizophrenia.
Anterior cingulate cortex
Adenosine monophosphate cyclic
cAMP response element-binding
Mitochondrial deoxyribonucleic acid
Messenger ribonucleic acid
Magnetic resonance spectroscopy
Polymerase chain reaction
Positron emission tomography
Regional cerebral blood flow
Reactive oxygen species
Mitochondrial disease results from a malfunction in biochemical cascade and the damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neuropsychiatrics disorders, such as bipolar disorder, depression and schizophrenia [3, 4, 6]. Several studies have demonstrated that abnormalities in energy metabolism lead to cellular degeneration . However, mitochondria are also involved in other essential processes such as apoptosis and calcium homeostasis . In this context, this review discusses energy impairment as a mechanism underlying the pathophysiology of some psychiatric disorders: bipolar disorder, depression and schizophrenia.
Bipolar disorder is a prevalent psychiatric disorder characterized by alternating episodes of mania and depression [8, 9]. Bipolar disorder can be further subdivided into bipolar I disorder, a recurrent mood disorder, featuring either one or more manic or mixed episodes, or both manic and mixed episodes and at least one major depressive episode; or bipolar II disorder, characterized by one or more episodes of major depression and at least one hypomanic episode . According to the criteria of DSM IV, the prevalence of bipolar depression is 0.6% for bipolar disorder I and 1.7% for bipolar disorder II, whereas for unipolar depression it is 21%. According to the Bonetto et al. studies , with strict criteria for the length of hypomania, the prevalence remains in 0.6% for bipolar disorder I and around 20% for unipolar depression, but it is 5.3% for bipolar disorder II.
The mortality rate of the disease is two to three times higher than that of the general population. About one-third of individuals affected by bipolar disorder admit to at least one suicide attempt . The prevention of recurrences and the acute management of depressive and manic episodes are the major goals in the treatment of bipolar disorder . The acute manic symptoms of bipolar disorder require rapid therapeutic intervention , which can provide stabilization and relief from the broad range of symptoms associated with mania. In order to achieve this, patients should be treated with the optimal dose of the chosen medication as quickly as possible to maximize their chance of treatment success [14, 15].
The difficulty of investigating bipolar disorder lies in the fact that diagnosis and treatment have changed over time, and controversies and unresolved differences exist about many issues related to the identification, clinical presentation, course, and management of the disorder . Recent studies have demonstrated that changes in intracellular pathways that regulate neuronal transmission, plasticity and survival are associated with the pathophysiology of bipolar disorder [16–18]. Magnetic resonance spectroscopy (MRS) provides a unique opportunity to gain insight into the biochemical pathology of bipolar disorder . MRS studies have demonstrated reduced N-acetylaspartate (a marker of neuronal viability) in the hippocampus of bipolar disorder patients [20, 21], suggesting that bipolar disorder may be associated with hippocampus dysfunction.
In addition, it has been hypothesized that bipolar disorder is associated with mitochondrial dysfunction [22, 23]. It is well known that abnormalities in respiratory complexes activity and energy production may lead to cellular degeneration . Konradi et al.  reported decreased expression of nuclear gene coding for enzymatic complexes responsible for oxidative phosphorylation and reduced expression of nuclear genes related to proteasome degradation in the hippocampi of nine subjects affected by bipolar disorder. In this context, it has been recently demonstrated the important role of mitochondria in sequestering increased intracellular calcium caused by agonist stimulation . It is possible that the mitochondrial dysfunction suggested by MRS research in bipolar disorder is directly related to these previously observed alterations of calcium response and intracellular signaling systems in bipolar patients . Moreover, in vivo MRS studies have demonstrated a decrease in both pH and high-energy phosphates, such as phosphocreatine and ATP, in the frontal and temporal lobes of bipolar disorder subjects [24–27].
Positron emission tomography (PET) studies of bipolar individuals in the manic state reported decreased regional cerebral blood flow (rCBF) in the right ventral temporal lobe [8, 28], orbitofrontal cortex , and frontal regions, when compared to normal controls . A study performed by Blumberg et al.  verified that manic patients present higher rCBF in the left dorsal anterior cingulate cortex (ACC) and left head of the caudate, when compared to a separate sample of euthymic bipolar patients. Although PET research cannot identify the etiology of these metabolic differences in bipolar patients, it is possible that they are related to the mitochondrial dysfunction suggested by MRS studies . Using a quantitative polymerase chain reaction (PCR) method, a study by Kato et al.  found a significantly higher ratio of deleted to wild-type mitochondrial deoxyribonucleic acid (mtDNA) in the cerebral cortex of patients with bipolar disorder, when compared to age-matched controls. More recently, post mortem studies in hippocampus  and cortex  of bipolar disorder patients showed a decrease in the expression of nuclear genes coding for messenger ribonucleic acid (mRNA) of the mitochondrial respiratory chain enzymes.
It has long been recognized that the administration of amphetamine induces manic symptoms in both normal human volunteers  and bipolar disorder patients . An adequate animal model of bipolar disorder should resemble some features of a manic episode such as euphoria, irritability, aggressiveness, hyperactivity, insomnia or increased sexual drive. Considering the difficulty of modeling the highly complex mood swinging nature of bipolar disorder, the psychostimulant-induced hyperactivity is the best established animal model of mania . In this context, it has been recently demonstrated that citrate synthase, an important enzyme of Krebs cycle, is inhibited by amphetamine administration in rat brain. The results indicated that mood stabilizing effects of lithium and valproate might involve mitochondrial stabilization. According to this study, the inhibition of activity of citrate synthase may be probably related to the pathophysiology of this disease . There are some studies showing that amphetamine induces changes in various systems, such as signaling pathways and kinases and phosphatases activities, and that mood stabilizers prevent and/or reverse some of these biochemical and other behavioral effects caused by amphetamine [37–41].
If the inhibition on brain energy metabolism really occurs in bipolar disorder patients, it is tempting to speculate that this reduction may be probably related to the pathophysiology of this disease. Furthermore, the understanding of bipolar disorder in terms of mitochondrial dysfunction may greatly affect the usage of the treatments currently available.
Unipolar depressive disorders encompass a range of features that strongly suggest a neurobiologic substrate. These features include symptoms such as disturbances in sleep, appetite, or sexual desire, constipation, loss of interest and pleasure, crying, negative rumination, and slowing of speech and action, fatigue, poor concentration and also apparent abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis . These changes must last a minimum of 2 weeks and interfere considerably with work and family relationships. Moreover, depression seems to have genetic antecedents, also suggesting a biologic contribution to its origin .
The noradrenergic and serotonergic systems originate deep in the brain and fan out over almost the entire brain, suggesting a system capable of modulating many areas of feeling, thinking, and behaving . The early antidepressants block the reuptake of norepinephrine and serotonin by the presynaptic neuron. The immediate effects of this pharmacologic action are to increase the availability of norepinephrine and serotonin in the synapse and to increase stimulation of the postsynaptic neuron . Inhibitors of the enzyme monoamine oxidase were also discovered to have antidepressant properties. This enzyme catabolyzes norepinephrine and serotonin in their respective presynaptic neurons, and such inhibition could be expected to increase the availability of neurotransmitters. These discoveries led to a major theory of depression known as the monoamine deficiency hypothesis , which postulates a deficiency in serotonin or norepinephrine neurotransmission in the brain . Monoaminergic neurotransmission is mediated by serotonin (5-hydroxytryptamine 1A [5-HT1A] and 5-hydroxytryptamine 1B [5-HT1B]) or norepinephrine released from presynaptic neurons. Serotonin is synthesized from tryptophan, with the first step in the synthetic pathway catalyzed by tryptophan hydroxylase; norepinephrine is synthesized from tyrosine, with the first step catalyzed by tyrosine hydroxylase .
Findings in patients with depression that support the monoamine-deficiency hypothesis include a relapse of depression with inhibition of tyrosine hydroxylase or depletion of dietary tryptophan, an increased frequency of a mutation affecting the brain-specific form of tryptophan hydroxylase, increased specific ligand binding to monoamine oxidase, subsensitive 5-HT1A receptors, malfunctioning 5-HT1B receptors, polymorphisms of the serotonin-reuptake transporter associated with depression, an inadequate response of G proteins to neurotransmitter signals, and reduced levels of adenosine monophosphate cyclic (cAMP), inositol, and cAMP response element-binding (CREB) in postmortem brains [49, 50]. The HPA axis and its final effector system, glucocorticoids, are essential component of an individual’s capacity to cope with stress and in fact, a hyperactivity of the HPA axis is observed in the majority of patients with depression [55, 56].
However, the exact pathophysiology of depression is not clearly understood. Several works also suggest brain metabolism impairment as a mechanism underlying depression. Gardner et al.  showed a significant decrease of mitochondrial ATP production rates and mitochondrial enzyme ratios in muscle compared to controls in major depressive disorder patients. Since life stressors contribute in some fashion to depression and are an extension of what occurs normally, chronic stress has been used as an animal model of depression. It has been reported that brain Na+, K+-ATPase is inhibited by chronic variate stress . Moreover, Madrigal et al.  also reported that complexes I-III and II-III of mitochondrial respiratory chain were inhibited in rat brain after chronic stress (immobilization for six hours during 21 days). It has also been recently reported inhibition of mitochondrial respiratory chain complexes I, III and IV activities after chronic variate stress for 40 days . Moreover, complex II activity was not affected. It is well known that mitochondrial oxidative phosphorylation system generates free radicals and the electron transport chain itself is vulnerable to damage by free radicals . The oxidative damage induced by stress may be either the cause or the consequence of the mitochondrial dysfunction [4, 5, 61]. In this context, Madrigal et al.  reported glutathione depletion and lipid peroxidation in brain of rats after chronic stress for 21 days. Rezin et al.  also reported that the complexes I, III and IV were inhibited only in cerebral cortex and cerebellum. Several works showed that cerebral cortex and cerebellum present abnormalities in subjects with mood disorders. Konarski et al.  reported that regional deficits in the frontal lobe, particularly in the anterior cingulate and the orb to frontal cortex, appear to consistently differentiate patients with mood disorders from the general population. Several structural neuroimaging studies have consistently identified regional abnormalities in subjects with mood disorders [62, 63]. The cerebellum is typically involved in motor control. Moreover, clinical and research findings have also shown cerebellar involvement in a number of cognitive and affective processes .
The effect of electroconvulsive shock (an animal model for electroconvulsive therapy) showed increased activities of mitochondrial respiratory chain complexes II and IV , and inhibition on creatine kinase activity in brain of rats .
Schizophrenia is a devastating mental disorder with a life prevalence of approximately 1%, which commonly follows a chronic course with an onset at late adolescence, heterogeneity and comorbidity with other mental disorders frequently renders schizophrenia difficult to diagnose . This disorder is characterized by disturbed thoughts and perception, alongside cognitive and emotional decline associated with a severe reduction in occupational and social functioning, and in coping abilities. These symptoms are typically conceptualized as falling into two broad categories, positive and negative symptoms .
The etiology and pathophysiology of schizophrenia remain unknown, but impaired mitochondrial function and as a consequence impaired cellular energy state, is an attractive hypothesis for explaining the pathophysiology of schizophrenia . Several studies also observed alterations in brain metabolic rates in other brain regions including the thalamus and the basal ganglia [7, 69, 70], leading to the suggestion of an impairment in the fronto-striatal-thalamic circuitry in schizophrenia rather than in a specific brain region [71–73]. Moreover, the mitochondria are of a ubiquitous nature and the respiratory chain has a dual genetic basis, i.e., the mitochondrial and the nuclear DNA . In some studies of schizophrenia, reduced levels of ATP were found in the frontal lobe, temporal lobe and basal ganglia, as detected by 31P-MRS [75–77]. Ultra structural studies in the caudate nucleus and the prefrontal cortex showed the decreased volume density of mitochondria in oligodendrogliocytes in schizophrenia . Any factor adversely affecting the ability of mitochondria to carry out these fundamental tasks is likely to have detrimental consequences for brain development and function . Several clinical, genetic and neuroimaging studies implicate mitochondrial dysfunction in the pathophysiology of bipolar disorder and schizophrenia. These studies shown that platelet mitochondrial complex I, which is the first complex of the mitochondrial electron transport system, is significantly increased in schizophrenic patients in the acute state, and not in patients with affective disorders. Disease-state dependent alterations in mitochondrial complex I activity was positively correlated with the severity of patients’ positive symptoms . Uranova and Aganova  studied the ultra structure of autopsied anterior limbic cortex from schizophrenic patients and reported deformation and reduction in the number of mitochondria. Kung and Roberts  showed that in the caudate nucleus and the putamen throughout the neuropil, mitochondrial density was significantly reduced by approximately 20% in a mixed sample of drug-treated and off-drug cases as compared to control level. Still, it has been reported that a mitochondrial DNA (mtDNA) deletion of 4977 bp, known as the ‘common deletion’, is associated with both mental illnesses. Consequently, mitochondrial dysfunction can lead to impairment in one or more of these factors and thereby to cellular abnormal activity or even death. In addition, mitochondria have their own DNA (mtDNA), which encodes the genes for the enzyme subunits of the mitochondrial respiratory chain . A lack of normal age-related accumulation of this deletion in schizophrenia and increased occurrence of the common deletion in bipolar disorder has been reported. However, even in the affected bipolar samples, the levels of common deletion were relatively small, indicating that the common deletion did not play a pathophysiological role in respiratory function . A parallel transcriptomics, proteomics and metabolomics approach was employed on human brain tissue to explore the molecular disease signatures. Almost half the altered proteins identified by proteomics were associated with mitochondrial function and oxidative stress responses . This was mirrored by transcriptional and metabolite perturbations. Studies have suggested that reactive oxygen species (ROS) production may play a role in the pathophysiology of many neuropsychiatric disorders, such as bipolar disorder and schizophrenia. In addition, there is an emerging body of data indicating that bipolar disorder and schizophrenia may be associated with mitochondrial dysfunction. These findings suggest that amphetamine-induced mitochondrial ROS generation may be a useful model to investigate the hypothesis of altered brain energy metabolism associated with bipolar disorder and schizophrenia . Alterations of mitochondrial oxidative phosphorylation in schizophrenia have been reported in several brain regions [74, 85] and also in platelets . Abnormal mitochondrial morphology, size and density have all been reported in the brains of schizophrenic individuals .
Some models have been used to simulate schizophrenic disorders, such as ketamine, amphetamine or dopaminergic psychostimulants administration . In contrast to amphetamine, which mimics only the positive symptoms of the disease, sub anesthetic doses of the N-methyl-D-aspartate (NMDA) antagonist ketamine have been reported to produce positive and negative symptoms and cognitive impairments consistent with those seen in schizophrenia . In this context, it has been recently reported that creatine kinase activity is decreased in rat brain (prefrontal cortex, cerebellum, hippocampus, striatum and cerebral cortex) after sub anesthetic doses of ketamine (L. Canever et al., 2008, Inhibitory effect of subanesthesic doses of ketamine on creatine kinase activity, unpublished results). Moreover, some evidences suggest changed levels of high-energy phosphates in the cortex of schizophrenic patients . Burbaeva et al.  also showed that creatine kinase was altered in the brain of patients with schizophrenia, suggesting that this decrease leads to disturbances in brain energy metabolism and is involved in the pathogenesis of this disorder.
The authors would like to thank UNESC (Brazil), FAPESC (Brazil) and CNPq (Brazil) that supported the studies of our group that are cited in this review.