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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: 2.55). 12/2008; 34(6):1021-9. DOI: 10.1007/s11064-008-9865-8
Source: PubMed

ABSTRACT 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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    • "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 · 5.55 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 · 2.71 Impact Factor
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    • "Several investigators have proposed that mitochondrial dysfunction is related to the pathophysiology of MRD (Rezin et al. 2009). The main role of mitochondria, cytoplasmic organelle, is as a producer of energy, a process that generates high levels of reactive oxygen species. "
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    ABSTRACT: Depressive disorders, especially major recurrent depression (MRD), are among the most common psychiatric diseases and are expected to become the second most common form of psychiatric illness by the year 2020. The mechanisms responsible for the development of depression have been discussed widely, and evidence suggests heterogenic and mixed etiologies for the disease. Depressive disorder is characterized by inflammatory processes, oxidative and nitrosative stress (O&NS), and disturbances in the pro- and antioxidant equilibrium. Patients diagnosed with major depressive disorder (MDD) using DSM-IV criteria and patients diagnosed with recurrent depressive disorder according to the ICD-10 criteria as well as individuals who suffer with major depression meeting other scale display a decrease in the levels of total glutathione, uric acid, and ascorbic acid, a decrease in the levels of glutathione peroxidase (GPX), an increase in malondialdehyde (MDA) levels, high free radical generation, an increase in 8-hydroxy-deoxyguanosine, and an increase in nitrite and nitrate levels. Antidepressants affect pro- and antioxidant equilibrium and are able to reduce O&NS and inflammation. The involvement of inflammation and O&NS in depression, as well as a 70 % effectiveness in the treatment of MRD with antidepressants, and the anti-inflammatory activity of antidepressants all suggest the coadministration of antidepressants and anti-inflammatory drugs. Clinically, novel approaches to reduce free radical production are needed to improve the therapeutic strategies that target O&NS. Collates illustrated reviews of free radical induced cellular damage in a variety of tissues and organs Includes detailed expert discussion of molecular and cellular mechanisms Discusses the success and limitations of the use of antioxidants in several clinical settings and considers site-specific therapies Brings readers insights into various diseases where free radicals are thought to play a role The focus of this collection of illustrated reviews is to discuss the systems biology of free radicals and anti-oxidants. Free radical induced cellular damage in a variety of tissues and organs is reviewed, with detailed discussion of molecular and cellular mechanisms. The collection is aimed at those new to the field, as well as clinicians and scientists with long standing interests in free radical biology. A feature of this collection is that the material also brings insights into various diseases where free radicals are thought to play a role. There is extensive discussion of the success and limitations of the use of antioxidants in several clinical settings. Content Level » Research Keywords » RNS - ROS - Systems biology - anti-oxidants - disease - free radicals - organ - oxidative stress Related subjects » Human Physiology - Immunology - Internal Medicine - Medicine - Pharmacology & Toxicology Table of contents SECTIONS: General topics.- Embryology and Neonatal.- Hematology/Tissue repair.- Dermatology.- Genitourinary.- Cancer.- Pulmonary.- Musculoskeletal.- Gastrointestinal.- Immunology and Inflammation.- Endocrinology.- Plant-derived Anti-Oxidants.- Exercise, Ear, Nose and Throat.- Clinical Aspects.
    Systems Biology of Free Radicals and Antioxidants, 2014 edited by Laher, Ismail (Ed, 06/2014: chapter Oxidative Stress in Depression: pages Pages 2369-2395; Springer-Verlag Berlin Heidelberg 2014., ISBN: ISBN-10: 3642300170, ISBN-13: 978-3642300172
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