Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia

doi:10.1016/J.IJDEVNEU.2010.08.007

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Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia

Journal Article•DOI•

Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia

Hayley B. Clay¹, Stephanie E. Sillivan¹, Christine Konradi•Institutions (1)

Vanderbilt University¹

01 May 2011-International Journal of Developmental Neuroscience (NIH Public Access)-Vol. 29, Iss: 3, pp 311-324

TL;DR: The role of mitochondria during brain development and the effect of current drugs for mental illness on mitochondrial function are described and the evidence for mitochondrial abnormalities in BPD and SZ is reviewed.

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About: This article is published in International Journal of Developmental Neuroscience.The article was published on 2011-05-01 and is currently open access. It has received 339 citations till now. The article focuses on the topics: Mitochondrial disease & Mitochondrial DNA.

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Journal Article•DOI•

Dendritic spine pathology in schizophrenia.

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Jill R. Glausier¹, David A. Lewis¹•Institutions (1)

University of Pittsburgh¹

22 Oct 2013-Neuroscience

TL;DR: Dendritic spine alterations have been identified in multiple brain regions in schizophrenia, but are best characterized in layer 3 of the neocortex, where pyramidal cell spine density is lower, suggesting disturbances in the molecular mechanisms that underlie spine formation, pruning, and/or maintenance are likely.

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461 citations

Cites background from "Mitochondrial dysfunction and patho..."

...However, mitochondria dysfunction has also been implicated in other psychiatric illnesses, such as bipolar disorder (Clay et al., 2011), which have not as yet been shown to have lower spine density....
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...Multiple sources of information point to mitochondrial dysfunction in schizophrenia (Clay et al., 2011), including altered lactate levels in cerebrospinal fluid (Regenold et al....
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Journal Article•DOI•

A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures.

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Daniel A. Rossignol, Richard E. Frye¹•Institutions (1)

University of Arkansas for Medical Sciences¹

01 Apr 2012-Molecular Psychiatry

TL;DR: Evaluation of trends between the four major areas and the four comparison areas demonstrated that the largest relative growth was in immune dysregulation/inflammation, oxidative stress, toxicant exposures, genetics and neuroimaging.

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Abstract: Recent studies have implicated physiological and metabolic abnormalities in autism spectrum disorders (ASD) and other psychiatric disorders, particularly immune dysregulation or inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures (‘four major areas’). The aim of this study was to determine trends in the literature on these topics with respect to ASD. A comprehensive literature search from 1971 to 2010 was performed in these four major areas in ASD with three objectives. First, publications were divided by several criteria, including whether or not they implicated an association between the physiological abnormality and ASD. A large percentage of publications implicated an association between ASD and immune dysregulation/inflammation (416 out of 437 publications, 95%), oxidative stress (all 115), mitochondrial dysfunction (145 of 153, 95%) and toxicant exposures (170 of 190, 89%). Second, the strength of evidence for publications in each area was computed using a validated scale. The strongest evidence was for immune dysregulation/inflammation and oxidative stress, followed by toxicant exposures and mitochondrial dysfunction. In all areas, at least 45% of the publications were rated as providing strong evidence for an association between the physiological abnormalities and ASD. Third, the time trends in the four major areas were compared with trends in neuroimaging, neuropathology, theory of mind and genetics (‘four comparison areas’). The number of publications per 5-year block in all eight areas was calculated in order to identify significant changes in trends. Prior to 1986, only 12 publications were identified in the four major areas and 51 in the four comparison areas (42 for genetics). For each 5-year period, the total number of publications in the eight combined areas increased progressively. Most publications (552 of 895, 62%) in the four major areas were published in the last 5 years (2006–2010). Evaluation of trends between the four major areas and the four comparison areas demonstrated that the largest relative growth was in immune dysregulation/inflammation, oxidative stress, toxicant exposures, genetics and neuroimaging. Research on mitochondrial dysfunction started growing in the last 5 years. Theory of mind and neuropathology research has declined in recent years. Although most publications implicated an association between the four major areas and ASD, publication bias may have led to an overestimation of this association. Further research into these physiological areas may provide insight into general or subset-specific processes that could contribute to the development of ASD and other psychiatric disorders.

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444 citations

Journal Article•DOI•

How Might Circadian Rhythms Control Mood? Let Me Count the Ways...

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Colleen A. McClung¹•Institutions (1)

University of Pittsburgh¹

15 Aug 2013-Biological Psychiatry

TL;DR: This review will summarize recent data that implicate the circadian system as a vital regulator of a variety of systems that are thought to play a role in the development of mood disorders.

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390 citations

Journal Article•DOI•

An updated meta-analysis of oxidative stress markers in bipolar disorder

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Nicole C. Brown¹, Ana Cristina Andreazza¹, L. Trevor Young¹•Institutions (1)

University of Toronto¹

15 Aug 2014-Psychiatry Research-neuroimaging

TL;DR: The role of oxidative stress in bipolar disorder, especially to DNA, RNA, and lipids, is supported by a meta-analysis of studies that measured oxidative stress markers in BD patients compared to healthy controls.

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Abstract: Despite its debilitating symptoms, the pathophysiology of bipolar disorder (BD) remains unclear. One consistently compelling finding, however, has been the presence of oxidative stress. In the present investigation, we conducted a meta-analysis of studies that measured oxidative stress markers in BD patients compared to healthy controls. Search terms and selection criteria were determined a priori to identify and include all studies that measured a marker of oxidative stress in BD compared to healthy controls. Eight markers were included: superoxide dismutase, catalase, protein carbonyl, glutathione peroxidase, 3-nitrotyrosine, lipid peroxidation, nitric oxide, and DNA/RNA damage. A meta-analysis of standardized means was conducted using a random-effects model with generic inverse weighting. Between-study heterogeneity, publication bias, and sensitivity analyses were also examined for each marker. Twenty-seven papers were included in the meta-analysis, which comprised a total of 971 unique patients with BD and 886 healthy controls. Lipid peroxidation, DNA/RNA damage, and nitric oxide were significantly increased in BD patients compared to healthy controls. Additionally, the effect size for lipid peroxidation was very high. Publication bias was not detected for any of the markers. The main limitations in this meta-analysis are the high degree of heterogeneity between studies and the small number of studies used in the analysis of some markers. Additionally, the sensitivity analysis indicated that some results are not very robust. The results from this meta-analysis support the role of oxidative stress in bipolar disorder, especially to DNA, RNA, and lipids.

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255 citations

Cites background from "Mitochondrial dysfunction and patho..."

...The involvement of mitochondrial dysfunction in BD is supported by several lines of evidence such as reduced expression of several mitochondrial electron transport chain subunits, increased mtDNA deletion and mutation, reduced pH, and decreased levels of high-energy phosphates in the brain of BD patients (Clay et al., 2011)....
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...…dysfunction in BD is supported by several lines of evidence such as reduced expression of several mitochondrial electron transport chain subunits, increased mtDNA deletion and mutation, reduced pH, and decreased levels of high-energy phosphates in the brain of BD patients (Clay et al., 2011)....
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Journal Article•DOI•

The role of methionine on metabolism, oxidative stress, and diseases

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Yordan Martínez¹, Yordan Martínez², Xue Li², Gang Liu², Peng Bin², Wenxin Yan², Dairon Más, M. Valdivié, Chien-An Andy Hu, Wenkai Ren², Yulong Yin³, Yulong Yin² - Show less +8 more•Institutions (3)

Agricultural University of Havana¹, Chinese Academy of Sciences², Hunan Normal University³

19 Sep 2017-Amino Acids

TL;DR: Methionine restriction prevents altered methionine/transmethylation metabolism, thereby decreasing DNA damage and carcinogenic processes and possibly preventing arterial, neuropsychiatric, and neurodegenerative diseases.

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Abstract: Methionine is an aliphatic, sulfur-containing, essential amino acid, and a precursor of succinyl-CoA, homocysteine, cysteine, creatine, and carnitine. Recent research has demonstrated that methionine can regulate metabolic processes, the innate immune system, and digestive functioning in mammals. It also intervenes in lipid metabolism, activation of endogenous antioxidant enzymes such as methionine sulfoxide reductase A, and the biosynthesis of glutathione to counteract oxidative stress. In addition, methionine restriction prevents altered methionine/transmethylation metabolism, thereby decreasing DNA damage and carcinogenic processes and possibly preventing arterial, neuropsychiatric, and neurodegenerative diseases. This review focuses on the role of methionine in metabolism, oxidative stress, and related diseases.

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253 citations

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References

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Journal Article•DOI•

A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine

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Douglas C. Wallace¹•Institutions (1)

University of California, Irvine¹

14 Nov 2005-Annual Review of Genetics

TL;DR: The mitochondria provide a direct link between the authors' environment and their genes and the mtDNA variants that permitted their forbears to energetically adapt to their ancestral homes are influencing their health today.

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Abstract: Life is the interplay between structure and energy, yet the role of energy deficiency in human disease has been poorly explored by modern medicine. Since the mitochondria use oxidative phosphorylation (OXPHOS) to convert dietary calories into usable energy, generating reactive oxygen species (ROS) as a toxic by-product, I hypothesize that mitochondrial dysfunction plays a central role in a wide range of age-related disorders and various forms of cancer. Because mitochondrial DNA (mtDNA) is present in thousands of copies per cell and encodes essential genes for energy production, I propose that the delayed-onset and progressive course of the agerelated diseases results from the accumulation of somatic mutations in the mtDNAs of post-mitotic tissues. The tissue-specific manifestations of these diseases may result from the varying energetic roles and needs of the different tissues. The variation in the individual and regional predisposition to degenerative diseases and cancer may result from the interaction of modern dietary caloric intake and ancient mitochondrial genetic polymorphisms. Therefore the mitochondria provide a direct link between our environment and our genes and the mtDNA variants that permitted our forbears to energetically adapt to their ancestral homes are influencing our health today.

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3,016 citations

"Mitochondrial dysfunction and patho..." refers background in this paper

...Mitochondrial DNA mutations accumulate throughout a lifetime, while mtDNA levels and mitochondrial function tend to decline with age (Wallace, 2005)....
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...Excess ROS production can also occur during nutrient overload, when electron transport chain complexes are oversaturated with electrons and release electrons promiscuously (Russell et al., 2002; Wallace, 2005)....
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...The 16.6-kB mitochondrial genome (mtDNA) contains 37 genes: 22 transfer RNAs (tRNAs), two ribosomal RNAs (rRNAs), seven genes for proteins of the electron transport chain complex I, one complex III gene, three complex IV genes, and two complex V genes (Wallace, 2005)....
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...Transcription of mitochondrial RNA is thought to occur in a similar manner as replication, and after synthesis of a polycistronic transcript, tRNAs fold and are cleaved, producing individual mRNAs for each gene, which are polyadenylated before translation by mitochondrial ribosomes (Wallace, 2005)....
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...Detrimental mitochondrial mutations impair the effectiveness of OXPHOS, and highly OXPHOS-reliant tissues such as the brain, pancreas, and muscle are more commonly affected (Wallace, 2005)....
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Journal Article•DOI•

Mitochondrial diseases in man and mouse.

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Douglas C. Wallace¹•Institutions (1)

Emory University¹

05 Mar 1999-Science

TL;DR: The essential role of mitochondrial oxidative phosphorylation in cellular energy production, the generation of reactive oxygen species, and the initiation of apoptosis has suggested a number of novel mechanisms for mitochondrial pathology.

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Abstract: Over the past 10 years, mitochondrial defects have been implicated in a wide variety of degenerative diseases, aging, and cancer. Studies on patients with these diseases have revealed much about the complexities of mitochondrial genetics, which involves an interplay between mutations in the mitochondrial and nuclear genomes. However, the pathophysiology of mitochondrial diseases has remained perplexing. The essential role of mitochondrial oxidative phosphorylation in cellular energy production, the generation of reactive oxygen species, and the initiation of apoptosis has suggested a number of novel mechanisms for mitochondrial pathology. The importance and interrelationship of these functions are now being studied in mouse models of mitochondrial disease.

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2,950 citations

"Mitochondrial dysfunction and patho..." refers background in this paper

...Hydrogen ions pass back into the matrix through complex V (ATP synthase), an energy-producing event used to synthesize ATP from ADP and inorganic phosphate (Brandon et al., 2005a; Wallace, 1999, 2005)....
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Journal Article•DOI•

Regulation of cell death: the calcium-apoptosis link.

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Sten Orrenius¹, Boris Zhivotovsky¹, Pierluigi Nicotera²•Institutions (2)

Karolinska Institutet¹, University of Leicester²

01 Jul 2003-Nature Reviews Molecular Cell Biology

TL;DR: The dual role of Ca2+ in living organisms is discussed in this paper, where it has been shown that cellular Ca 2+ overload, or perturbation of intracellular Ca2 + compartmentalization, can cause cytotoxicity and trigger either apoptotic or necrotic cell death.

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Abstract: To live or to die? This crucial question eloquently reflects the dual role of Ca2+ in living organisms--survival factor or ruthless killer. It has long been known that Ca2+ signals govern a host of vital cell functions and so are necessary for cell survival. However, more recently it has become clear that cellular Ca2+ overload, or perturbation of intracellular Ca2+ compartmentalization, can cause cytotoxicity and trigger either apoptotic or necrotic cell death.

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2,685 citations

Journal Article•DOI•

Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations.

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H. Bernheimer¹, Birkmayer W, O. Hornykiewicz², Kurt A. Jellinger¹, F. Seitelberger¹ - Show less +1 more•Institutions (2)

University of Vienna¹, University of Toronto²

01 Dec 1973-Journal of the Neurological Sciences

TL;DR: A clinical, morphological and neurochemical correlative study in patients with Parkinson's syndrome and Huntington's chorea is reported in this paper, where positive correlations can be established, within a certain range, between the severity of individual Parkinsonian symptoms (especially akinesia and tremor) and the degree, and also the site, of the disturbance of dopamine metabolism within the nuclei of the basal ganglia; and the sensitivity of the patients to levodopa's acute anti-akinesia effect.

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2,395 citations

Journal Article•DOI•

Microdomains of intracellular Ca2+: molecular determinants and functional consequences.

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Rosario Rizzuto¹, Tullio Pozzan•Institutions (1)

University of Ferrara¹

01 Jan 2006-Physiological Reviews

TL;DR: This review discusses the structural and functional bases that generate the subcellular heterogeneity in cellular Ca(2+) levels at rest and under stimulation, and focuses on the molecular mechanisms that lead to the generation of cytoplasmic Ca( 2+) microdomains, focusing on their different sub cellular location, mechanism of generation, and functional role.

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Abstract: Calcium ions are ubiquitous and versatile signaling molecules, capable of decoding a variety of extracellular stimuli (hormones, neurotransmitters, growth factors, etc.) into markedly different int...

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1,104 citations

"Mitochondrial dysfunction and patho..." refers background in this paper

...In addition to providing cellular energy, mitochondria form microdomains with calcium (Ca2+) influx sites to buffer cytosolic Ca2+ (Rizzuto and Pozzan, 2006)....
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...Ca2+ released into the cytosol from either external sources such as NMDA receptors or from the endoplasmic reticulum is taken up by mitochondria and released slowly, preventing high levels of cytosolic Ca2+ from inducing stress and excitotoxicity (Baron et al., 2003; Rizzuto and Pozzan, 2006)....
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