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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] ABSTRACT: Monoamine deficit and mitochondrial dysfunction may underlie depression. Serotoninergic neurons from raphe nuclei project widely and may be involved in depression. This study used chronic unpredictable stress (CUS) in rats as a model of depression to assess the effects of CUS, exercise and fluoxetine on mitochondrial function and serotonin levels in the raphe nuclei. Rats were divided into 4 groups (6 per group): control (C); depression (D), CUS for 28days; depression+exercise (DE), treadmill exercises from days 11-28 of CUS; depression+fluoxetine (DF), fluoxetine (5mg/kg/d i.g.) from days 11-28 of CUS. Behavioral changes were assessed using body weight, sucrose consumption tests (anhedonia) and open field tests (locomotor/exploratory behavior). Raphe nucleus mitochondrial function was determined using the respiratory control ratio, ATP synthesis rate, and activities of superoxide dismutase and glutathione peroxidase. Serotonin levels were measured in the raphe nuclei and hippocampus. On day 28 of CUS, body weight were higher in group C than in groups D, DE and DF (P<0.001), and higher in group DE than in group D or DF (P<0.05). Sucrose consumption were higher in group C than in groups D, DE and DF (P<0.001), higher in group DE than in groups D (P<0.001) or DF (P<0.05), and higher in group DF than in group D (P<0.05). All measures of mitochondrial function were increased in group D compared with the other groups (P<0.01). Hippocampal serotonin was lower in group D than in the other groups (P<0.01); levels in the raphe nuclei were elevated in group DE compared with the remaining groups (P<0.001). CUS in rats may cause overactivation of mitochondria in the raphe nuclei, and exercise training may suppress these changes.
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