Mitochondrial Dysfunction and Psychiatric Disorders

Laboratório de Fisiopatologia Experimental, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciuma, SC, Brazil.
Neurochemical Research (Impact Factor: 2.59). 12/2008; 34(6):1021-9. DOI: 10.1007/s11064-008-9865-8
Source: PubMed


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.

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    • "However, although our previous experiments revealed significant enhancements in 17-HSD10 brain expression or in total CSF levels in AD patients when compared to age-matched controls, changes were found not to be fully specific to AD [18] [19] [20]. In particular, we have observed similar, although less pronounced, alterations in hippocampal 17-HSD10 expression in patients with schizophrenia [18] or in CSF levels of people with autoimmune neuroinflammatory multiple sclerosis [19], i.e., in two diseases involving mitochondrial dysfunction [21] [22]. The specificity of the complexes 17-HSD10-A to AD was unfortunately greater only in comparison with multiple sclerosis (i.e., in the disease without elevated A) [19], but not with various neuroinflammatory diseases accompanied by markedly elevated extracellular A levels [20]. "
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    ABSTRACT: Background: Overexpression of the mitochondrial enzyme 17-hydroxysteroid dehydrogenase type 10 (17-HSD10, which is also known as the intracellular amyloid- peptide (A-) binding protein) is observed in cortical or hippocampal regions of patients with Alzheimer's disease (AD). It appears that 17-HSD10 may play a role in the pathogenesis of AD. Objective: We investigated the possibility that levels of 17-HSD10 in cerebrospinal fluid could be a prospective biomarker of AD. Methods:We estimated the enzyme levels in 161 people (15 non-demented controls, 52 people with mild cognitive impairment (MCI), 35 people with probable AD, or 59 people with other types of dementia) and compared them with those of A-1-42, tau, and phospho-tau. Results:We found significantly higher levels of 17-HSD10 in people with MCI due to AD (to 109.9%), with AD (to 120.0%), or with other types of dementia (to 110.9%) when compared to the control group. The sensitivity of the new biomarker to AD was 80.0%, and the specificity was 73.3% (compared to controls) or 52.5-59.1% (compared to other types of dementia). Results of multiple linear regression and of correlation analysis revealed AD-mediated changes in links between 17-HSD10 and Mini Mental State Examination score. Conclusion: It seems that changes in 17-HSD10 start many years before symptom onset, analogous to those in A-1-42, tau, or phospho-tau and that the levels are a relatively highly sensitive but unfortunately less specific biomarker of AD. A role of 17-HSD10 overexpression in AD is discussed.
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    • "Moreover, chronic stress induced an inhibition to the respiratory chain in the mitochondria in the brain (Madrigal et al., 2001). Mitochondrial dysfunction caused by changes in biochemical cascade or the damage to the mitochondrial electron transport chain has been suggested to be an important pathogenic factor for the psychiatric disorders, particularly in bipolar disorders and depression (Rezin et al., 2009). Moreover, food supplements, such as B12 or folate, which protects mitochondrial "
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    ABSTRACT: ABSTRACT Numerous studies have linked severe stress to the development of major depressive disorder (MDD), and suicidal behaviors. Furthermore, recent preclinical studies from our laboratory and others have demonstrated that in rodents, chronic stress and the stress hormone cortisol has caused oxidative damage to mitochondrial function and membrane lipids in the brain. Mitochondria play a key role in synaptic neurotransmitter signaling by providing adenosine triphosphate (ATP), mediating lipid and protein synthesis, buffering intracellular calcium, and regulating apoptotic and resilience pathways. Membrane lipids are similarly essential to central nervous system (CNS) function, because cholesterol, polyunsaturated fatty acids, and sphingolipids form a lipid raft region, a special lipid region on the membrane that mediates neurotransmitter signaling through G-protein coupled receptors and ion channels. Low serum cholesterol levels, low antioxidant capacity, and abnormal early morning cortisol levels are biomarkers consistently associated with both depression and suicidal behaviors. In this review, we summarize the manner in which nutrients can protect against oxidative damage to mitochondria and lipids in the neuronal circuits associated with cognitive and affective behaviors. These nutrients include ω3 fatty acids, antioxidants (vitamin C and zinc), members of the vitamin B family (Vitamin B12 and folic acid) and magnesium. Accumulating data have shown that these nutrients can enhance neurocognitive function, and may have therapeutic benefits for depression and suicidal behaviors. A growing body of studies suggests the intriguing possibility that regular consumption of these nutrients may help prevent the onset of mood disorders and suicidal behaviors in vulnerable individuals, or significantly augment the therapeutic effect of available antidepressants. These findings have important implications for the health of both military and civilian populations.
    Critical Reviews in Food Science and Nutrition 11/2014; DOI:10.1080/10408398.2013.876960 · 5.18 Impact Factor
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    • "Complex I, III and IV inhibition in cerebral cortex and cerebellum reversed by ketamine. Rezin et al. (2009) Mouse, 6 weeks of chronic mild stress. "
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    ABSTRACT: Major depressive disorder (MDD) is an important public health problem affecting 350 million people worldwide. After decades of study, the pathophysiology of MDD remains elusive, resulting in treatments that are only 30-60 % effective. This review summarizes the emerging evidence that implicates impaired mitochondrial bioenergetics as a basis for MDD. It is suggested that impaired mitochondrial bioenergetic function contributes to the pathophysiology of MDD via several potential pathways including: genetics/genomics, inflammation, oxidative stress, and alterations in neuroplasticity. A discussion of mitochondrial bioenergetic pathways that lead to MDD is provided. Evidence is reviewed regarding the mito-toxic or mito-protective impact of various antidepressant medications currently in use. Opportunities for further research on novel therapeutic approaches, including mitochondrial modulators, as stand-alone or adjunct therapy for reducing depression are suggested. In conclusion, while there is substantial evidence linking mitochondrial bioenergetics and MDD, there are currently no clear mitochondrial phenotypes or biomarkers to use as guides in targeting therapies beyond individuals with MDD and known mitochondrial disorders toward the general population of individuals with MDD. Further study is needed to develop these phenotypes and biomarkers, to identify therapeutic targets, and to test therapies aimed at improving mitochondrial function in individuals whose MDD is to some extent symptomatic of impaired mitochondrial bioenergetics.
    Journal of Bioenergetics 09/2014; 47(1-2). DOI:10.1007/s10863-014-9584-6 · 3.21 Impact Factor
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