Dataset Information

Mitochondrial Dysfunction in Depression.

ABSTRACT: BACKGROUND:Depression is the most debilitating neuropsychiatric disorder with significant impact on socio-occupational and well being of individual. The exact pathophysiology of depression is still enigmatic though various theories have been put forwarded. There are evidences showing that mitochondrial dysfunction in various brain regions is associated with depression. Recent findings have sparked renewed appreciation for the role of mitochondria in many intracellular processes coupled to synaptic plasticity and cellular resilience. New insights in depression pathophysiology are revolving around the impairment of neuroplasticity. Mitochondria have potential role in ATP production, intracellular Ca2+ signalling to establish membrane stability, reactive oxygen species (ROS) balance and to execute the complex processes of neurotransmission and plasticity. So understanding the various concepts of mitochondrial dysfunction in pathogenesis of depression indubitably helps to generate novel and more targeted therapeutic approaches for depression treatment. OBJECTIVE:The review was aimed to give a comprehensive insight on role of mitochondrial dysfunction in depression. RESULT:Targeting mitochondrial dysfunction and enhancing the mitochondrial functions might act as potential target for the treatment of depression. CONCLUSION:Literature cited in this review highly supports the role of mitochondrial dysfunction in depression. As impairment in the mitochondrial functions lead to the generation of various insults that exaggerate the pathogenesis of depression. So, it is useful to study mitochondrial dysfunction in relation to mood disorders, synaptic plasticity, neurogenesis and enhancing the functions of mitochondria might show promiscuous effects in the treatment of depressed patients.

SUBMITTER: Bansal Y

PROVIDER: S-EPMC4981740 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Mitochondrial Dysfunction in Depression.

Bansal Yashika Y Kuhad Anurag A

Current neuropharmacology 20160101 6

<h4>Background</h4>Depression is the most debilitating neuropsychiatric disorder with significant impact on socio-occupational and well being of individual. The exact pathophysiology of depression is still enigmatic though various theories have been put forwarded. There are evidences showing that mitochondrial dysfunction in various brain regions is associated with depression. Recent findings have sparked renewed appreciation for the role of mitochondria in many intracellular processes coupled t ...[more]

PMID: 26923778

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Project description:We characterized the global response of plants carrying a mitochondrial dysfunction induced by the expression of the unedited form of the ATP synthase 9 subunit. The u-ATP9 transgene driven by A9 and Apetala3 promoters induce mitochondrial dysfunction revealed by a decrease in both oxygen uptake and ATP levels, with an increase in ROS and a concomitant oxidative stress response. The transcriptome analysis of young Arabidopsis flowers, validated by RT-PCR and enzymatic or functional tests, show dramatic changes in u-ATP9 plants. Both lines present a modification in the expression of several genes involved in carbon, lipid and cell wall metabolism, suggesting that an important metabolic readjustment occurs in plants with a mitochondrial dysfunction. Interestingly, transcript levels involved in mitochondrial biogenesis, protein synthesis, and degradation are affected. Moreover, several mRNA levels for transcription factors and DNA binding proteins were also changed. Some of them are involved in stress and hormone response, suggesting that several signaling pathways overlap. Indeed, the transcriptome data reveal that the mitochondrial dysfunction dramatically alters genes involved in signaling pathways, including those involved in ethylene, absicic acid and auxin signal transduction. Our data suggest that the mitochondrial dysfunction model used in this rapport may be useful to uncover the retrograde signaling mechanism between the nucleus and mitochondria in plant cells. Arabidopsis oligonucleotide microarrays fabricated by the University of Arizona contain 26,000 oligonucleotides (http://www.ag.arizona.edu/microarray/). RNA was isolated from 6-week-old flowers from u-ATP9 and wt plants. The experimental (mutant) and reference (wild type) RNA samples were reverse-transcribed and directly labeled with either Cy5-dUTP or Cy3-dUTP fluorescent dye (GE Healthcare), using random hexamer primers (Invitrogen). Excess nucleotides and primers were removed using QIAquick PCR Purification Kit (Qiagen). Labeled samples were mixed and then hybridized to microarray for 15 h at 60°C. The slides were washed at room temperature in three wash steps: 2 x SSC, 0.5% SDS; 0.5 x SSC; and 0.05 x SSC for 5 min each with gentle shaking. The slides were scanned with a GenePix 4000B Scanner (Axon Instruments Inc., Union City, CA). Normalization between the Cy3 and Cy5 fluorescent dye emission channels was achieved by adjusting the levels of both image intensities. The experiments were repeated four times with samples from different experiments, as biological replicates. In dye swapping experiments, the RNA samples from different experiments were reciprocally labeled, both as a biological and technical repetition for comparing the reproducibility of the experiments. Hybridization intensities for each microarray element were measured using ScanAlyze 4.24 (available at http://genome-www4.stanford.edu/MicroArray/SMD/restech.html). The two channels were normalized in log space using the z-score normalization on a 95% trimmed data set. We removed unreliable spots according to the following criteria: spots flagged as having false intensity caused by dust or background on the array were removed; and spots for which intensity was less than three fold above background were also eliminated. Data from multiple experiments were normalized (Bolstad, 2003) and signals from spots from different experiments were statistically analyzed using Significance Analysis of Microarrays using the one class response (SAM, http://www-stat.stanford.edu/~tibs/SAM/), cut at a false discovery rate < 10% (Tusher, 2001).

Project description:ContextImpaired mitochondrial function may influence processes highly dependent on energy, such as neurodevelopment, and contribute to autism. No studies have evaluated mitochondrial dysfunction and mitochondrial DNA (mtDNA) abnormalities in a well-defined population of children with autism.ObjectiveTo evaluate mitochondrial defects in children with autism.Design, setting, and patientsObservational study using data collected from patients aged 2 to 5 years who were a subset of children participating in the Childhood Autism Risk From Genes and Environment study in California, which is a population-based, case-control investigation with confirmed autism cases and age-matched, genetically unrelated, typically developing controls, that was launched in 2003 and is still ongoing. Mitochondrial dysfunction and mtDNA abnormalities were evaluated in lymphocytes from 10 children with autism and 10 controls.Main outcome measuresOxidative phosphorylation capacity, mtDNA copy number and deletions, mitochondrial rate of hydrogen peroxide production, and plasma lactate and pyruvate.ResultsThe reduced nicotinamide adenine dinucleotide (NADH) oxidase activity (normalized to citrate synthase activity) in lymphocytic mitochondria from children with autism was significantly lower compared with controls (mean, 4.4 [95% confidence interval {CI}, 2.8-6.0] vs 12 [95% CI, 8-16], respectively; P = .001). The majority of children with autism (6 of 10) had complex I activity below control range values. Higher plasma pyruvate levels were found in children with autism compared with controls (0.23 mM [95% CI, 0.15-0.31 mM] vs 0.08 mM [95% CI, 0.04-0.12 mM], respectively; P = .02). Eight of 10 cases had higher pyruvate levels but only 2 cases had higher lactate levels compared with controls. These results were consistent with the lower pyruvate dehydrogenase activity observed in children with autism compared with controls (1.0 [95% CI, 0.6-1.4] nmol × [min × mg protein](-1) vs 2.3 [95% CI, 1.7-2.9] nmol × [min × mg protein](-1), respectively; P = .01). Children with autism had higher mitochondrial rates of hydrogen peroxide production compared with controls (0.34 [95% CI, 0.26-0.42] nmol × [min × mg of protein](-1) vs 0.16 [95% CI, 0.12-0.20] nmol × [min × mg protein](-1) by complex III; P = .02). Mitochondrial DNA overreplication was found in 5 cases (mean ratio of mtDNA to nuclear DNA: 239 [95% CI, 217-239] vs 179 [95% CI, 165-193] in controls; P = 10(-4)). Deletions at the segment of cytochrome b were observed in 2 cases (ratio of cytochrome b to ND1: 0.80 [95% CI, 0.68-0.92] vs 0.99 [95% CI, 0.93-1.05] for controls; P = .01).ConclusionIn this exploratory study, children with autism were more likely to have mitochondrial dysfunction, mtDNA overreplication, and mtDNA deletions than typically developing children.

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Mitochondrial Dysfunction in Depression.

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Mitochondrial Dysfunction in Depression.

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