Impaired mitochondrial function in psychiatric disorders

Manji, Husseini K.; Kato, Takeshi; Prospero, Nicholas A. Di; Ness, Seth; Beal, M. Flint; Krams, Michael; Chen, Guang

doi:10.1038/nrn3229

Cited by 409 publications

(333 citation statements)

References 172 publications

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“…Furthermore, we have shown that this GR dependent regulation of mitochondrial mRNA can occur in response to environmental stress, a known factor in a number of neurologic and psychiatric diseases (41). These findings have implications for a variety of phenomena in neuroscience, from synaptic plasticity, by which local control of mitochondrial activity could be altered, to neurodegenerative diseases in which mitochondrial dysfunction is widely implicated and in which stress can be a contributing factor (10,42). Acute Immobilization Stress.…”

Section: Discussionmentioning

confidence: 99%

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

Hunter

Seligsohn

Rubin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

130

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Glucocorticoids (GCs) are involved in stress and circadian regulation, and produce many actions via the GC receptor (GR), which is classically understood to function as a nuclear transcription factor. However, the nuclear genome is not the only genome in eukaryotic cells. The mitochondria also contain a small circular genome, the mitochondrial DNA (mtDNA), that encodes 13 polypeptides. Recent work has established that, in the brain and other systems, the GR is translocated from the cytosol to the mitochondria and that stress and corticosteroids have a direct influence on mtDNA transcription and mitochondrial physiology. To determine if stress affects mitochondrially transcribed mRNA (mtRNA) expression, we exposed adult male rats to both acute and chronic immobilization stress and examined mtRNA expression using quantitative RT-PCR. We found that acute stress had a main effect on mtRNA expression and that expression of NADH dehydrogenase 1, 3, and 6 (ND-1, ND-3, ND-6) and ATP synthase 6 (ATP-6) genes was significantly down-regulated. Chronic stress induced a significant up-regulation of ND-6 expression. Adrenalectomy abolished acute stress-induced mtRNA regulation, demonstrating GC dependence. ChIP sequencing of GR showed that corticosterone treatment induced a dose-dependent association of the GR with the control region of the mitochondrial genome. These findings demonstrate GR and stress-dependent transcriptional regulation of the mitochondrial genome in vivo and are consistent with previous work linking stress and GCs with changes in the function of brain mitochondria.nuclear receptors | allostasis | mitochondrial plasticity | brain metabolism | mitochondrial transcription

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Section: Discussionmentioning

confidence: 99%

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

Hunter

Seligsohn

Rubin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

130

View full text Add to dashboard Cite

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“…NCALD, also known as VSNL3, is a high-affinity Ca 2 þ sensor that has been found to interact with cytoskeletal proteins (Paterlini et al, 2000). In SCZ, evidence for brain mitochondrial dysfunction has been reported, including findings of impaired brain energy metabolism, developmental deviations, abnormal neurotransmission, and connectivity (Manji et al, 2012;Rosenfeld et al, 2011), along with mitochondrial hypoplasia, oxidative phosphorylation system imbalance, and altered mitochondrial protein expression (Karry et al, 2004;Prabakaran et al, 2004). Consistent with these reports, we detected alterations of several subunits of the electron transport chain complex I in the frontal cortex tissue from PCP-treated rats (NDUFA9, NDUFS3, NDUFV1, and NDUFV2).…”

Section: Biological Functions P-values Proteins Biological Functions mentioning

confidence: 99%

A Combined Metabonomic and Proteomic Approach Identifies Frontal Cortex Changes in a Chronic Phencyclidine Rat Model in Relation to Human Schizophrenia Brain Pathology

Wesseling

Chan

Tsang

et al. 2013

Neuropsychopharmacol

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Current schizophrenia (SCZ) treatments fail to treat the broad range of manifestations associated with this devastating disorder. Thus, new translational models that reproduce the core pathological features are urgently needed to facilitate novel drug discovery efforts. Here, we report findings from the first comprehensive label-free liquid-mass spectrometry proteomic-and proton nuclear magnetic resonance-based metabonomic profiling of the rat frontal cortex after chronic phencyclidine (PCP) intervention, which induces SCZ-like symptoms. The findings were compared with results from a proteomic profiling of post-mortem prefrontal cortex from SCZ patients and with relevant findings in the literature. Through this approach, we identified proteomic alterations in glutamate-mediated Ca 2 þ signaling (Ca 2 þ /calmodulin-dependent protein kinase II, PPP3CA, and VISL1), mitochondrial function (GOT2 and PKLR), and cytoskeletal remodeling (ARP3). Metabonomic profiling revealed changes in the levels of glutamate, glutamine, glycine, pyruvate, and the Ca 2 þ regulator taurine. Effects on similar pathways were also identified in the prefrontal cortex tissue from human SCZ subjects. The discovery of similar but not identical proteomic and metabonomic alterations in the chronic PCP rat model and human brain indicates that this model recapitulates only some of the molecular alterations of the disease. This knowledge may be helpful in understanding mechanisms underlying psychosis, which, in turn, can facilitate improved therapy and drug discovery for SCZ and other psychiatric diseases. Most importantly, these molecular findings suggest that the combined use of multiple models may be required for more effective translation to studies of human SCZ.

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“…Mitochondria, the source of 95% of the ATP in the brain, are involved in many brain disorders including SZ (Anglin et al, 2012;Manji et al, 2012). Mitochondria function as a dynamic network constantly undergoing fusion and fission, the balance of which is important in maintaining their structural integrity and function (Legros et al, 2002 a role in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network (Bach et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Synaptic Proteins in the Postmortem Anterior Cingulate Cortex in Schizophrenia: Relationship to Treatment and Treatment Response

Barksdale

Lahti

Roberts

2014

Neuropsychopharmacol

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The anterior cingulate cortex (ACC) is one of several brain regions that are abnormal in schizophrenia (SZ). Here we compared markers of synapse and mitochondrial function using western blots of postmortem ACC in: 1) normal controls (NCs, n ¼ 13) vs subjects with SZ (n ¼ 25); NC, treatment-resistant SZ, and treatment-responsive SZ; and 3) NC and SZ treated with typical or atypical antipsychotic drugs (APDs). Protein levels of synaptophysin, mitofusin-2, vGLUT1, and calcineurin did not differ between the NC and SZ group as a whole, or the NCs vs the SZ group divided by treatment response or type of APDs. In several cases, the levels of vGLUT1 were minuscule or absent. The proportion of NCs lacking vGLUT1 was significantly less than that of the SZ groups. There were several positive correlations across all subjects between: 1) synaptophysin and vGLUT1; 2) synaptophysin and calcineurin; 3) synaptophysin and mitofusin; and 4) calcineurin and mitofusin. Synaptophysin and calcineurin were positively correlated in responders, and this correlation was significantly stronger than that in treatment-resistant SZ subjects or in NCs. Synaptophysin and calcineurin were positively correlated in SZ patients on atypical APDs; this correlation was significantly stronger than that in SZ patients on typical APDs or in NCs. Mitofusin-2 and calcineurin were positively correlated in SZ patients on atypical APDs and in NCs; this correlation was stronger in SZ patients on atypical rather than typical APDs or in NCs. The correlation between these proteins, which have roles in synaptic vesicle cycling, glutamate transmission, mitochondrial fusion, and calcium buffering, is complex and was differentially regulated among the groups.

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Impaired mitochondrial function in psychiatric disorders

Cited by 409 publications

References 172 publications

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

A Combined Metabonomic and Proteomic Approach Identifies Frontal Cortex Changes in a Chronic Phencyclidine Rat Model in Relation to Human Schizophrenia Brain Pathology

Synaptic Proteins in the Postmortem Anterior Cingulate Cortex in Schizophrenia: Relationship to Treatment and Treatment Response

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