Mitochondrial alterations and neuropsychiatric disorders
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, Italy. Current Medicinal Chemistry
(Impact Factor: 3.85).
Mitochondria are membrane-enclosed organelle found in most eukaryotic cells, where they generate the majority of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy. In addition, they are involved in a range of other processes, such as signalling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth. Mitochondria have been implicated in several neuropsychiatric disorders, in particular, depression, anxiety, schizophrenia, autism, and Alzheimer's dementia. Furthermore, the presence of mutations at the level of mitochondrial or nuclear DNA (mtDNA and nDNA, respectively) has been linked to personality disorders, behavioral disturbances, thought alterations, impulsivity, learning impairment, cognitive failures until dementia. The aim of this paper is to review the literature on the relationship between psychiatric symptoms or syndromes and mtDNA mutations or mitochondrial alterations, while highlighting novel therapeutic targets for a broad range of disorders.
Available from: Brian Dean
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ABSTRACT: Increasing evidence suggests that epigenetic factors have critical roles in gene regulation in neuropsychiatric disorders and in aging, both of which are typically associated with a wide range of gene expression abnormalities. Here, we have used chromatin immunoprecipitation-qPCR to measure levels of acetylated histone H3 at lysines 9/14 (ac-H3K9K14), two epigenetic marks associated with transcriptionally active chromatin, at the promoter regions of eight schizophrenia-related genes in n=82 postmortem prefrontal cortical samples from normal subjects and those with schizophrenia and bipolar disorder. We find that promoter-associated ac-H3K9K14 levels are correlated with gene expression levels, as measured by real-time qPCR for several genes, including, glutamic acid decarboxylase 1 (GAD1), 5-hydroxytryptamine receptor 2C (HTR2C), translocase of outer mitochondrial membrane 70 homolog A (TOMM70A) and protein phosphatase 1E (PPM1E). Ac-H3K9K14 levels of several of the genes tested were significantly negatively associated with age in normal subjects and those with bipolar disorder, but not in subjects with schizophrenia, whereby low levels of histone acetylation were observed in early age and throughout aging. Consistent with this observation, significant hypoacetylation of H3K9K14 was detected in young subjects with schizophrenia when compared with age-matched controls. Our results demonstrate that gene expression changes associated with psychiatric disease and aging result from epigenetic mechanisms involving histone acetylation. We further find that treatment with a histone deacetylase (HDAC) inhibitor alters the expression of several candidate genes for schizophrenia in mouse brain. These findings may have therapeutic implications for the clinical use of HDAC inhibitors in psychiatric disorders.
Translational Psychiatry 12/2011; 1(12):e64. DOI:10.1038/tp.2011.61 · 5.62 Impact Factor
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ABSTRACT: Developmental neuronal cell death is critically regulated by the pro-death protein Bax. Bax-/- mice exhibit increased neuron number, the elimination of several neural sex differences, and altered socio-sexual behaviours. Here we examined the effects of Bax gene deletion on anxiety and defensive behaviours by comparing the responses of male and female wildtype and Bax-/- mice to two different tests. On the elevated plus maze, Bax-/- mice of both sexes made more entries into and spent more time in the outer portion of open arms, indicating decreased anxiety compared to wildtype animals. Next, we exposed mice to two odours: trimethylthiazoline (TMT), an olfactory component of fox feces that rodents find aversive, and butyric acid (BA), an aversive odour without ecological significance. Each odour was presented individually and all animals were tested with both odours in a counterbalanced design. TMT was consistently more aversive than BA across a variety of behaviours (e.g., mice spent less time close to the odour source). Overall, Bax -/- mice showed fewer stretch approaches to both TMT and BA than wildtypes, but they avoided the odour source more (e.g., fewer contacts and less time spent in proximity). Finally, no effect of genotype was seen in baseline olfactory behaviour; all mice were able to locate a buried food item, demonstrating that Bax-/- mice do not have impaired olfaction per se. Collectively, these data suggest a change in strategy with anxiety and defensive behaviours in Bax-/- mice, indicating that alterations in cell number affect more general mechanisms of fear and anxiety in addition to behaviours directly related to reproduction.
Behavioural brain research 11/2012; 239(1). DOI:10.1016/j.bbr.2012.10.056 · 3.03 Impact Factor
Available from: Michael Seibenhener
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ABSTRACT: Affective spectrum and anxiety disorders have come to be recognized as the most prevalently diagnosed psychiatric disorders. Among a suite of potential causes, changes in mitochondrial energy metabolism and function have been associated with such disorders. Thus, proteins that specifically change mitochondrial functionality could be identified as molecular targets for drugs related to treatment for affective spectrum disorders. Here, we report generation of transgenic mice overexpressing the scaffolding and mitophagy related protein Sequestosome1 (SQSTM1/p62) or a single point mutant (P392L) in the UBA domain of SQSTM1/p62. We show that overexpression of SQSTM1/p62 increases mitochondrial energy output and improves transcription factor import into the mitochondrial matrix. These elevated levels of mitochondrial functionality correlate directly with discernible improvements in mouse behaviors related to affective spectrum and anxiety disorders. We also describe how overexpression of SQSTM1/p62 improves spatial learning and long term memory formation in these transgenic mice. These results suggest that SQSTM1/p62 provides an attractive target for therapeutic agents potentially suitable for the treatment of anxiety and affective spectrum disorders.
Behavioural brain research 04/2013; 248. DOI:10.1016/j.bbr.2013.04.006 · 3.03 Impact Factor
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