The somatic common deletion in mitochondrial DNA is decreased in schizophrenia

Mamdani, Firoza; Rollins, Brandi; Sequeira, Pedro; Vawter, Marquis P.

doi:10.1016/j.schres.2014.08.026

Cited by 31 publications

(44 citation statements)

References 59 publications

(97 reference statements)

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“…The mitochondria common deletion levels increase with age in the brain, and the present results confirm those prior reports [9,10,13,31]. We did not find a significant decrease in mtDNA common deletion in SZ after correction for age in PFC.…”

Section: Discussionsupporting

confidence: 92%

“…As in our previous work using SYBR Green qPCR [13], this redesigned SYBR Green mtDNA copy number assay shows similar ranges of mtDNA copy number estimates in DLPFC samples (range 632-3,513 mtDNA copies per single copy number of the nuclear gene ALB). The mean and standard deviation for the entire current sample was 1,608 ± 541 mtDNA copies per nuclear genome in PFC.…”

Section: Resultssupporting

confidence: 55%

“…Associations between the mtDNA 4,977-bp common deletion load in the brain and neuropsychiatric disorders have also been reported [8,9,10,11]. The mtDNA common deletion levels have been shown to increase in the brain with advanced aging [12,13]. However, we have previously observed that the age-related increase in the common deletion in brain was significant in control subjects but was not observed in SZ [13,14,15,16,17].…”

Section: Introductionmentioning

confidence: 99%

“…The mtDNA common deletion levels have been shown to increase in the brain with advanced aging [12,13]. However, we have previously observed that the age-related increase in the common deletion in brain was significant in control subjects but was not observed in SZ [13,14,15,16,17]. This SZ phenotype might be due to a lower activity of mitochondria in the brain of subjects with SZ that leads to a lower production of the mtDNA common deletion.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

Rollins¹,

Morgan²,

Hjelm³

et al. 2017

Complex Psychiatry

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Subjects with schizophrenia (SZ) and bipolar disorder (BD) show decreased protein and transcript levels for mitochondrial complex I. In vitro results suggest antipsychotic and antidepressant drugs may be responsible. We measured complex I activity in BD, SZ, and controls and presence of antipsychotic and antidepressant medications, mitochondrial DNA (mtDNA) copy number, and the mtDNA “common deletion” in the brain. Complex I activity in the prefrontal cortex was decreased by 45% in SZ compared to controls (p = 0.02), while no significant difference was found in BD. Complex I activity was significantly decreased (p = 0.01) in pooled cases (SZ and BD) that had detectable psychotropic medications and drugs compared to pooled cases with no detectable levels. Subjects with age at onset in their teens and psychotropic medications showed decreased (p < 0.05) complex I activity compared to subjects with an adult age at onset. Both SZ and BD groups displayed significant increases (p < 0.05) in mtDNA copy number compared to controls; however, common deletion burden was not altered. Complex I deficiency is found in SZ brain tissue, and psychotropic medications may play a role in mitochondrial dysfunction. Studies of medication-free first-episode psychosis patients are needed to elucidate whether mitochondrial pathophysiology occurs independent of medication effects.

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Section: Discussionsupporting

confidence: 92%

Section: Resultssupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

Rollins¹,

Morgan²,

Hjelm³

et al. 2017

Complex Psychiatry

Self Cite

View full text Add to dashboard Cite

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“…[45][46][47][48] Few studies have considered the structure and function of mitochondria in the NAcc in SZ. [49][50][51][52] Differential alterations in the basal ganglia have been reported in SZ, including increased mitochondrial activity in the NAcc of paranoid SZ subjects that was attributed to APD effects. 51 Despite the evidence for mitochondrial pathology in dorsal striatum in SZ, our structural findings do not indicate this pathology is present in the NAcc.…”

Section: Similar Morphological State Of Mitochondriamentioning

confidence: 98%

Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study

McCollum

Walker

Roche

et al. 2015

SCHBUL

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The cause of schizophrenia (SZ) is unknown and no single region of the brain can be pinpointed as an area of primary pathology. Rather, SZ results from dysfunction of multiple neurotransmitter systems and miswiring between brain regions. It is necessary to elucidate how communication between regions is disrupted to advance our understanding of SZ pathology. The nucleus accumbens (NAcc) is a prime region of interest, where inputs from numerous brain areas altered in SZ are integrated. Aberrant signaling in the NAcc is hypothesized to cause symptoms of SZ, but it is unknown if these abnormalities are actually present. Electron microscopy was used to study the morphology of synaptic connections in SZ. The NAcc core and shell of 6 SZ subjects and 8 matched controls were compared in this pilot study. SZ subjects had a 19% increase in the density of asymmetric axospinous synapses (characteristic of excitatory inputs) in the core, but not the shell. Both groups had similar densities of symmetric synapses (characteristic of inhibitory inputs). The postsynaptic densities of asymmetric synapses had 22% smaller areas in the core, but not the shell. These results indicate that the core receives increased excitatory input in SZ, potentially leading to dysfunctional dopamine neurotransmission and cortico-striatal-thalamic stimulus processing. The reduced postsynaptic density size of asymmetric synapses suggests impaired signaling at these synapses. These findings enhance our understanding of the role the NAcc might play in SZ and the interaction of glutamatergic and dopaminergic abnormalities in SZ.Key words: electron microscopy/anatomy/striatum/ synapseThe exact pathophysiology for the origin of schizophrenia (SZ) is unknown, however evidence from decades of research implies that interactions between multiple brain regions and multiple neurotransmitter systems are likely at play. One region that is implicated in SZ pathology is the nucleus accumbens (NAcc). The NAcc integrates signaling from multiple regions of the brain, receiving input from areas including the prefrontal cortex, hippocampus, amygdala, thalamus, and midbrain.1 Importantly, all of these areas have been associated with SZ, making the NAcc a prime region for integrating multiple disrupted areas to provide a comprehensive understanding of SZ pathology.2 Reciprocal connections between the NAcc and substantia nigra/ventral tegmental area (SN/VTA) indicate further importance of this region. Via these connections, the NAcc modulates dopaminergic input to the dorsal striatum, 3 and striatal dopamine (DA) dysfunction is a hallmark characteristic of the disorder.4 Though many studies have implicated the NAcc in SZ, none have been able to describe its circuitry.The purpose of this study was to provide the first ultrastructural analysis in postmortem human NAcc, and examine the neurocircuitry in the NAcc in SZ to establish the role this region may play in the disorder. We used stereological analysis of electron micrographs in postmortem SZ to analyze the organization an...

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Mitochondrial Dysfunction in Schizophrenia

Chung

2020

BioEssays

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Schizophrenia (SCZ) is a severe neurodevelopmental disorder affecting 1% of populations worldwide with a grave disability and socioeconomic burden. Current antipsychotic medications are effective treatments for positive symptoms, but poorly address negative symptoms and cognitive symptoms, warranting the development of better treatment options. Further understanding of SCZ pathogenesis is critical in these endeavors. Accumulating evidence has pointed to the role of mitochondria and metabolic dysregulation in SCZ pathogenesis. This review critically summarizes recent studies associating a compromised mitochondrial function with people with SCZ, including postmortem studies, imaging studies, genetic studies, and induced pluripotent stem cell studies. This review also discusses animal models with mitochondrial dysfunction resulting in SCZ-relevant neurobehavioral abnormalities, as well as restoration of mitochondrial function as potential therapeutic targets. Further understanding of mitochondrial dysfunction in SCZ may open the door to develop novel therapeutic strategies that can address the symptoms that cannot be adequately addressed by current antipsychotics alone.

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The somatic common deletion in mitochondrial DNA is decreased in schizophrenia

Cited by 31 publications

References 59 publications

Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study

Mitochondrial Dysfunction in Schizophrenia

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