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Cited by 399Mitochondrial Function and PathologyBipolar Disorder and TreatmentSchizophrenia research and treatment

Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia

Open access
Clay, Hayley B., Daws, Stephanie, Konradi, Christine·2011·International Journal of Developmental Neuroscience
DOI 10.1016/j.ijdevneu.2010.08.007PMC PMC3010320
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Abstract

Bipolar disorder (BPD) and schizophrenia (SZ) are severe psychiatric illnesses with a combined prevalence of 4%. A disturbance of energy metabolism is frequently observed in these disorders. Several pieces of evidence point to an underlying dysfunction of mitochondria: (i) decreased mitochondrial respiration; (ii) changes in mitochondrial morphology; (iii) increases in mitochondrial DNA (mtDNA) polymorphisms and in levels of mtDNA mutations; (iv) downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration; (v) decreased high‐energy phosphates and decreased pH in the brain; and (vi) psychotic and affective symptoms, and cognitive decline in mitochondrial disorders. Furthermore, transgenic mice with mutated mitochondrial DNA polymerase show mood disorder‐like phenotypes. In this review, we will discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BPD and SZ. We will furthermore describe the role of mitochondria during brain development and the effect of current drugs for mental illness on mitochondrial function. Understanding the role of mitochondria, both developmentally as well as in the ailing brain, is of critical importance to elucidate pathophysiological mechanisms in psychiatric disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes evidence that mitochondrial dysfunction—decreased respiration, altered morphology, mtDNA changes, downregulated OXPHOS genes, and altered energy metabolites—is implicated in bipolar disorder (BPD) and schizophrenia (SZ). It argues that mitochondrial pathology may be primary in some cases or secondary to other factors, and that mood stabilizers may improve while some antipsychotics may impair mitochondrial function.

Key findings

  • BPD and SZ, with a combined prevalence of approximately 4%, show disturbed energy metabolism and mitochondrial abnormalities including decreased mitochondrial respiration, changes in mitochondrial morphology, increased mtDNA polymorphisms/mutations, downregulation of nuclear-encoded mitochondrial mRNAs/proteins, and decreased high-energy phosphates and brain pH.
  • Disease-associated mtDNA variants include 5178A>C (associated with lower frontal lobe pH), 3243A>G (impaired tRNA aminoacylation with compensatory LARS2 upregulation), 3644T>C (decreased mitochondrial membrane potential and complex I activity), and 10398A>G (decreased mitochondrial matrix pH, higher baseline and post-stimulation mitochondrial Ca2+, and greater prevalence in lithium nonresponders). The 5 kB “common deletion” was increased in cortex of BPD probands and suicide victims in one study but not associated in another frontal cortex study.
  • Mitochondrial measures vary by brain region and cell type: rodent mtDNA copy numbers were 2,000–5,000 per cell in midbrain and striatum, ≥10,000 in spinal cord, striatum, and cortex, ~8,000 in medulla, and ≤4,000 in midbrain and cerebellum. Postmortem findings include smaller prefrontal cortex mitochondria in BPD, reduced oligodendrocyte mitochondrial numbers/volume in SZ prefrontal cortex, and fewer striatal mitochondria in SZ.
  • In vivo MRS studies found reduced frontal lobe pH and phosphomonoester levels in BPD, and increased cerebrospinal fluid lactate and glucose in BPD indicating a shift from mitochondrial respiration to glycolysis. Rodent models with neuron-specific mutant POLG showed mood disorder-like phenotypes ameliorated by lithium or electroconvulsive shock; mood stabilizers lithium and valproate improved mitochondrial function/antiapoptotic markers, whereas typical antipsychotics inhibited complex I.

Methods

  • Narrative review; no new experimental data were generated. The paper integrates genetic, physiological, postmortem, peripheral cell, imaging, and rodent studies relevant to mitochondrial function in BPD and SZ.
  • Data/sample: published literature on patients with BPD and SZ, postmortem brain tissue, peripheral cells and cell lines, magnetic resonance spectroscopy in living patients, and animal models. Specific cited studies include, for example, 439 schizophrenia families for parent-of-origin analysis and MRS studies of medicated and unmedicated BPD patients.
  • Main analysis: qualitative synthesis of evidence for mitochondrial abnormalities, mitochondrial genetics and physiology, oxidative stress, apoptosis, brain development, and effects of mood stabilizers and antipsychotics.

Limitations

  • The paper states that evidence for a primary mitochondrial pathology in BPD and SZ is mixed, and that studies cannot differentiate primary pathologies from secondary consequences. It also notes that some MRS sample sizes were small, that common deletion levels are low and results inconsistent, and that mtDNA SNP associations vary by ancestry/haplogroup with no particular gene or region consistently targeted.
  • Evident from the text: as a narrative review, it does not use a systematic search strategy or quantitative meta-analysis, and findings are drawn from heterogeneous tissues, populations, and study designs that are not directly comparable.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.ijdevneu.2010.08.007

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation

    First-generation antipsychotic drugs might have adverse effects on mitochondrial respiration.

    “first-generation antipsychotic drugs might have adverse effects on mitochondrial respiration (Bachmann et al., 2009; King et al., 2001; Maurer and Moller, 1997; Maurer et al., 2009; Pereira et al., 1992; Prince et al., 1997b; Sagara, 1998; Struewing et al., 2007; Valvassori et al.; Washizuka et al., 2009).”
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    • cites King et al., 2001

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    • cites Maurer and Moller, 1997

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  • Premisecitation

    A disturbance of energy metabolism is frequently observed in bipolar disorder and schizophrenia.

    “A disturbance of energy metabolism is frequently observed in these disorders.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cavelier et al., 1995

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    • cites Maurer et al., 2001

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    • cites Regenold et al., 2009

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  • Premisecitation

    Abnormalities in energy metabolism in bipolar disorder and schizophrenia have been found in functional assays and magnetic resonance spectroscopy studies.

    “Abnormalities in energy metabolism were found in functional assays (Cavelier et al., 1995; Maurer et al., 2001; Regenold et al., 2009) and in magnetic resonance spectroscopy studies (Dager et al., 2004; Deicken et al., 1995b; Frey et al., 2007; Jensen et al., 2006; Kato et al., 1993; Kato et al., 1995; Ongur et al., 2009; Stork and Renshaw, 2005; Yurgelun-Todd et al., 1996).”
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    • cites Cavelier et al., 1995

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    • cites Maurer et al., 2001

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    • cites Regenold et al., 2009

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  • Premisecitation

    Gene and protein expression studies point to a decrease of factors and enzymes involved in ATP generation and storage in bipolar disorder and schizophrenia.

    “Gene and protein expression studies point to a decrease of factors and enzymes involved in ATP generation and storage (Iwamoto et al., 2005; Karry et al., 2004; Klushnik et al., 1991; Konradi et al., 2004; MacDonald et al., 2006; Middleton et al., 2002; Mill et al., 2008; Pennington et al., 2008; Washizuka et al., 2005; Washizuka et al., 2009)”
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    • cites Iwamoto et al., 2005

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    • cites Karry et al., 2004

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    • cites Konradi et al., 2004

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  • Premisecitation

    Linkage analysis showed an association of both bipolar disorder and schizophrenia with genes involved in mitochondrial function.

    “linkage analysis showed an association of both disorders with genes involved in mitochondrial function (Kirk et al., 1999; Washizuka et al., 2003b; Washizuka et al., 2006; Xu et al., 2008; Zhang et al., 2009).”
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    • cites Kirk et al., 1999

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    • cites Washizuka et al., 2003b

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    • cites Xu et al., 2008

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  • Classified as probably not a substantial claim. 7

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    Interpretationreasoning

    The comorbidity and misdiagnosis of mitochondrial diseases with psychotic symptoms makes a strong case for a role of mitochondria in the clinical symptoms of psychosis.

    “The latter observation makes a particularly strong case for a role of mitochondria in the clinical symptoms of psychosis, as the primary disease-causing event in mitochondrial disorders is the mtDNA mutation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The primary disease-causing event in mitochondrial disorders is the mitochondrial DNA mutation.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Diseases caused by mitochondrial DNA mutations exhibit a matrilineal inheritance pattern.

    “diseases caused by mtDNA mutations exhibit a matrilineal inheritance pattern (Shao et al., 2008).”
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    • cites Shao et al., 2008

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    Premisecitation

    In cerebrospinal fluid from bipolar disorder patients, lactate and glucose levels were increased, indicating a shift from mitochondrial respiration to glycolysis.

    “In cerebrospinal fluid from BPD patients, lactate and glucose levels were increased, indicating a shift from mitochondrial respiration to glycolysis (Regenold et al., 2009).”
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    • cites Regenold et al., 2009

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    • Rests on an assumption: Impairment of oxidative phosphorylation activity causes accumulation of lactate and unprocessed glucose.

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    Premisecitation

    The response to metabolic stress is impaired in bipolar disorder, and this impairment is closely linked to mitochondria.

    “The response to metabolic stress is impaired in BPD, and this impairment is closely linked to mitochondria (Naydenov et al., 2007).”
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    • cites Naydenov et al., 2007

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    Premisecitation

    Common symptoms of mitochondrial disease include seizure, blindness, diabetes, muscle weakness, and cardiomyopathy.

    “Common symptoms of mitochondrial disease include seizure, blindness, diabetes, muscle weakness, and cardiomyopathy (DiMauro and Schon, 2008).”
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    • cites DiMauro and Schon, 2008

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    Premisecitation

    In the prefrontal cortex of bipolar disorder patients, complex I activity was impaired and associated with increased protein oxidation and nitration.

    “In the PFC of BPD patients, complex I activity was impaired and associated with increased protein oxidation and nitration (Andreazza et al., 2010).”
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    • cites Andreazza et al., 2010

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    Premisecitation

    Mitochondria form microdomains with calcium influx sites to buffer cytosolic calcium.

    “mitochondria form microdomains with calcium (Ca2+) influx sites to buffer cytosolic Ca2+ (Rizzuto and Pozzan, 2006).”
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    • cites Rizzuto and Pozzan, 2006

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    Premisecitation

    Although antipsychotic drugs can contribute to abnormal glucose metabolism, increased insulin resistance is a hallmark of psychotic disorders.

    “Although antipsychotic drugs can contribute to abnormal glucose metabolism (Newcomer, 2004), increased insulin resistance is a hallmark of psychotic disorders (Regenold et al., 2002).”
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    • cites Newcomer, 2004

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    • cites Regenold et al., 2002

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    Interpretationcitation

    Mitochondrial pathology in bipolar disorder and schizophrenia could be the consequence of genetic susceptibility, secondary to dysregulation of other neurotransmitter systems, or the result of environmental impacts such as exposure to toxins, famine, infections and substance abuse.

    “Mitochondrial pathology could be the consequence of genetic susceptibility (Brandon et al., 2005b; Ishizuka et al., 2006; James et al., 2004; Kvajo et al., 2008; Millar et al., 2005; Stoffel et al., 1996), secondary to dysregulation of other neurotransmitter systems (Ben-Shachar, 2002; Brenner-Lavie et al., 2009; Chen et al., 2008) or the results of environmental impacts such as exposure to toxins”
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    • cites Brandon et al., 2005b

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    • cites Brown and Derkits

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    Premisecitation

    Lymphocytes of bipolar disorder patients failed to respond to glucose deprivation while lymphocytes of normal controls responded with an upregulation of the elements of the electron transport chain.

    “Lymphocytes of BPD patients failed to respond to glucose deprivation while lymphocytes of normal controls responded with an upregulation of the elements of the electron transport chain (Naydenov et al., 2007).”
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    • cites Naydenov et al., 2007

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    Premisecitation

    Detrimental mitochondrial mutations impair the effectiveness of oxidative phosphorylation, and highly oxidative-phosphorylation-reliant tissues such as the brain, pancreas, and muscle are more commonly affected.

    “Detrimental mitochondrial mutations impair the effectiveness of OXPHOS, and highly OXPHOS-reliant tissues such as the brain, pancreas, and muscle are more commonly affected (Wallace, 2005).”
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    • cites Wallace, 2005

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    Premisecitation

    Mitochondrial DNA mutations accumulate throughout a lifetime, while mitochondrial DNA levels and mitochondrial function tend to decline with age.

    “Mitochondrial DNA mutations accumulate throughout a lifetime, while mtDNA levels and mitochondrial function tend to decline with age (Wallace, 2005).”
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    • cites Wallace, 2005

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    Premisecitation

    The common deletion occurs at low rates in non-diseased tissues and tends to increase in prevalence with age.

    “This deletion is one of the more prevalent mtDNA alterations, but occurs at low rates in non-diseased tissues and tends to increase in prevalence with age (Brandon et al., 2005a; Fuke et al., 2008; McInerny et al., 2009).”
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    • cites Brandon et al., 2005a

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    • cites McInerny et al., 2009

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    Premisecitation

    At baseline, roughly 1-5% of all oxygen consumed by the cell is converted to reactive oxygen species.

    “At baseline, roughly 1-5% of all oxygen consumed by the cell is converted to ROS (Lee and Wei, 2005)”
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    • cites Lee and Wei, 2005

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    Premisecitation

    Mitochondrial calcium overload can have detrimental effects on mitochondrial viability and ultimately causes cell death.

    “Mitochondrial Ca2+ overload, however, can have detrimental effects on mitochondrial viability and ultimately causes cell death (Orrenius et al., 2003).”
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    • cites Orrenius et al., 2003

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    Premisecitation

    Cells with high levels of the common deletion produce more reactive oxygen species when stimulated with an H2O2 insult, resulting in reduced cell viability.

    “the cells with high levels of this common deletion produce more reactive oxygen species when stimulated with an H2O2 insult, resulting in reduced cell viability (Jou et al., 2005; Liu et al., 2007; Wang and Lu, 2009).”
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    • cites Wang and Lu, 2009 source

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    Premisecitation

    Increased glutamate release during emotional situations and drug use, or decreased glucose levels during times of famine or deliberate starvation, are known risk factors for psychotic episodes.

    “These factors are known risk factors for psychotic episodes (Brown and Derkits; Brown and Yamamoto, 2003; Kroll, 2007; Kyle and Pichard, 2006)”
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    Interpretationreasoning

    The combination of elevated calcium levels and decreased ATP production will cause continuous cellular stress and reduce the ability to appropriately respond to temporary peaks in stressful stimuli such as increased glutamate release during emotional situations and drug use, or decreased glucose levels during times of famine or deliberate starvation.

    “The combination of elevated Ca2+ levels and decreased ATP production will cause continuous cellular stress and reduce the ability to appropriately respond to temporary peaks in stressful stimuli such as increased glutamate release during emotional situations and drug use, or decreased glucose levels during times of famine or deliberate starvation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The data suggest that mitochondrial DNA mutations in bipolar disorder and schizophrenia might be somatic rather than inherited, indicating either an overall increased vulnerability of mitochondrial DNA, or a higher exposure to DNA-damaging factors.

    “The data suggest that mtDNA mutations in BPD and SZ might be somatic rather than inherited, indicating either an overall increased vulnerability of mtDNA, or a higher exposure to DNA-damaging factors.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Large family studies have revealed increased rates of bipolar disorder and schizophrenia within families, suggesting a genetic vulnerability.

    “Large family studies have revealed increased rates of BPD and SZ within families, suggesting a genetic vulnerability (Gershon et al., 1982).”
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    • cites Gershon et al., 1982

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    Interpretationcitation

    Bipolar disorder mitochondria fail to maintain ATP output, which could heighten their sensitivity to mild insults.

    “BPD mitochondria fail to maintain ATP output, which could heighten their sensitivity to mild insults. (Plant et al., 2002)”
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    • cites Plant et al., 2002

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    Premisecitation

    In a group of 439 families affected by schizophrenia, rates of maternal and paternal inheritance patterns were roughly equal, and 52% of the families investigated had ill relatives on both sides of the family.

    “In a group of 439 families affected by SZ, rates of maternal and paternal inheritance patterns were roughly equal, and 52% of the families investigated had ill relatives on both sides of the family (DeLisi et al., 2000).”
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    • cites DeLisi et al., 2000

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    Premisecitation

    The percentage of mitochondrial DNA that contains the common deletion is quite low, which might make it difficult to obtain consistent results.

    “The percentage of mtDNA that contains the common deletion is quite low, which might make it difficult to obtain consistent results (McInerny et al., 2009).”
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    • cites McInerny et al., 2009

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    Interpretationreasoning

    Due to mosaicism, deletion levels can vary even between adjacent tissues and the results might not accurately reflect a potential pathology.

    “However, due to mosaicism, deletion levels can vary even between adjacent tissues and the results might not accurately reflect a potential pathology.”
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    Premisecitation

    Microarray analysis of peripheral blood mononuclear cells revealed that controls upregulated expression of electron transport genes in response to glucose deprivation, while cells from bipolar disorder patients failed to show any changes in mitochondrial gene expression.

    “Microarray analysis of the peripheral blood mononuclear cells revealed that controls upregulated expression of electron transport genes in response to glucose deprivation, while cells from BPD patients failed to show any changes in mitochondrial gene expression.”
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    • cites Naydenov et al., 2007

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    Premisecitation

    The schizophrenia- and bipolar-disorder-associated SNP 3243A>G, which lies in a leucine-tRNA gene, hampers the tRNA's aminoacylation, resulting in a compensatory upregulation of the leucyl-tRNA synthetase LARS2 that is seen both in cybrids containing 3243A>G and patient brains.

    “The SZ- and BPD-associated SNP 3243A>G, which lies in a leucine-tRNA gene, hampers the tRNA’s aminoacylation, resulting in a compensatory upregulation of the leucyl-tRNA synthetase LARS2 that is seen both in cybrids containing 3243A>G and patient brains (Munakata et al., 2005).”
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    • cites Munakata et al., 2005

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    Premisecitation

    Most groups identified different mitochondrial DNA single nucleotide polymorphisms across the mitochondrial genome as having disease associations, and no particular gene or region of mitochondrial DNA appears to be targeted.

    “Most groups identified different SNPs across the mitochondrial genome as having disease associations, and no particular gene or region of mtDNA appears to be targeted.”
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    • cites Amar et al., 2007

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    Interpretationreasoning

    In the cerebellum, a similar pattern of complex I subunit expression was observed, indicating that impairments in mitochondrial function may be widespread in individuals with these disorders.

    “In the cerebellum, a similar pattern of expression was observed, indicating that impairments in mitochondrial function may be widespread in individuals with these disorders.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Reductions in complex I protein expression correlate with reduced complex I function and increased protein oxidation and nitrosylation.

    “Reductions in complex I protein expression have also been found to correlate with reduced complex I function as well as increased protein oxidation and nitrosylation (Andreazza et al., 2010).”
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    • cites Andreazza et al., 2010

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    Interpretationcitation

    While evidence for a primary mitochondrial pathology in bipolar disorder and schizophrenia is mixed, evidence for psychotic and mood disorder symptoms in bona fide mitochondrial disorders is quite strong.

    “While the evidence for a primary mitochondrial pathology in BPD and SZ is mixed, the evidence for psychotic and mood disorder symptoms in bona fide mitochondrial disorders is quite strong”
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    • cites Campos et al., 2001

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    • cites Grover et al., 2006

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    Interpretationcitation

    Magnetic resonance spectroscopy studies of living patients circumvent the problem of low pH in postmortem samples and further support a link between brain pH and altered energy metabolism.

    “Magnetic resonance spectroscopy studies of living patients circumvent the problem of low pH in postmortem samples, and further support the notion of a link between brain pH and altered energy metabolism”
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    • cites Dager et al., 2004

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    • cites Kato et al., 1993

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    • cites Kato et al., 1998

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    Premisecitation

    The bipolar-disorder-associated 10398A>G polymorphism has been linked to decreased mitochondrial matrix pH, and higher baseline and post-stimulation mitochondrial calcium levels.

    “The BPD-associated 10398A>G polymorphism has been linked to decreased mitochondrial matrix pH, and higher baseline and post-stimulation mitochondrial Ca2+ levels (Kato and Kato, 2000; Kato et al., 2003; Kazuno et al., 2006; Kazuno et al., 2008; Washizuka et al., 2003a).”
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    • cites Kato and Kato, 2000

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    • cites Kato et al., 2003

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    • cites Kazuno et al., 2006

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    Interpretationcitation

    Disease-associated mutations in nuclear complex I genes have been identified and could contribute to observed reductions in complex I mRNA and protein expression levels.

    “Disease-associated mutations in nuclear complex I genes have been identified, for example, and could contribute to observed reductions in complex I mRNA and protein expression levels”
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    • cites Andreazza et al., 2010

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    • cites Ben-Shachar and Karry, 2008

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    • cites Karry et al., 2004

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    Premisecitation

    Similar downregulation of electron transport chain genes was observed in the hippocampus in schizophrenia, and downregulation of TCA cycle genes was observed in the prefrontal cortex.

    “Similar observations were made in the hippocampus in SZ (Altar et al., 2005), and a downregulation of TCA cycle genes was observed in the PFC (Middleton et al., 2002).”
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    • cites Altar et al., 2005

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    • cites Middleton et al., 2002

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    Interpretationreasoning

    Mitochondria are important factors of consideration in psychiatric disorders, though they might not necessarily be the primary cause.

    “The data demonstrate that mitochondria are important factors of consideration in psychiatric disorders, though they might not necessarily be the primary cause for these disorders.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The G72 protein localizes to mitochondria, and its overexpression can alter mitochondrial morphology by enhancing mitochondrial fragmentation.

    “The G72 protein localizes to mitochondria, and its overexpression can alter mitochondrial morphology by enhancing mitochondrial fragmentation (Kvajo et al., 2008).”
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    • cites Kvajo et al., 2008

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    Premisecitation

    Levels of creatine kinase mRNA were downregulated in the hippocampus and prefrontal cortex in bipolar disorder and schizophrenia, indicating altered energy metabolism.

    “It is thus not surprising that levels of creatine kinase mRNA were downregulated in the hippocampus and PFC in BPD and SZ (MacDonald et al., 2006), another indication of altered energy metabolism.”
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    • cites MacDonald et al., 2006

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    Interpretationcitation

    Comparison of medicated to unmedicated bipolar disorder patients revealed no significant difference in brain pH, suggesting mood stabilizers do not affect brain pH.

    “Although the sample size was small, comparison of medicated to unmedicated patients revealed no significant difference in brain pH, suggesting that mood stabilizers do not affect brain pH.”
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    • cites Kato et al., 1998

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    Interpretationreasoning

    A large number of studies have shown that the overall stability of mitochondria, the efficiency of OXPHOS, and the ability to buffer Ca2+ and neutralize ROS are affected in bipolar disorder and schizophrenia.

    “A large number of studies have shown that the overall stability of mitochondria, the efficiency of OXPHOS, and the ability to buffer Ca2+ and neutralize ROS, are affected in BPD and SZ.”
    Quote in the paperSubstantial claim

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    Premisecitation

    These behaviors were ameliorated by lithium treatment as well as by electroconvulsive shock treatment.

    “These behaviors were ameliorated by lithium treatment as well as by electroconvulsive shock treatment (Kasahara et al., 2008).”
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    • cites Kasahara et al., 2008

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    Interpretationreasoning

    While many of these disturbances could be secondary to lifestyle and drug treatment, evidence from animal and genetic studies indicates that in some cases mitochondrial pathology might be the primary cause.

    “While many of these disturbances could be secondary to lifestyle and drug treatment, evidence from animal and genetic studies indicates that in some cases mitochondrial pathology might be the primary cause.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Rodent behavioral abnormalities such as increased startle response and altered circadian behavior are valid analogues of human psychiatric symptoms.

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    Premisecitation

    Schizophrenia patients exhibit markers of increased lipid breakdown in frontal cortex, with increased PDEs in both frontal hemispheres and reduced PMEs in left frontal cortex.

    “Likewise, SZ patients exhibit markers of increased lipid breakdown in frontal cortex, with increased PDEs in both frontal hemispheres, and reduced PMEs in left frontal cortex.”
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    • cites Deicken et al., 1995c

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    Interpretationreasoning

    Although these studies cannot differentiate primary pathologies from secondary consequences, it is quite likely that mitochondrial pathologies are responsible for some of the symptoms observed in bipolar disorder and schizophrenia.

    “Although these studies cannot differentiate primary pathologies from secondary consequences, it is quite likely that mitochondrial pathologies are responsible for some of the symptoms observed in BPD and SZ.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Reduced PME and increased PDE levels were observed in the frontal cortex in bipolar disorder and schizophrenia patients, indicating increased lipid breakdown in the brain.

    “Reduced PME and increased phosphodiester (PDE) levels were observed in the frontal cortex in BPD and SZ patients, indicating increased lipid breakdown in the brain”
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    • cites Deicken et al., 1995b

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    • cites Fujimoto et al., 1992

      Not checked in the free run.

    • cites Klemm et al., 2001 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Antipsychotic drugs do not improve the mitochondrial pathology observed in schizophrenia, and some of these drugs inhibit complex I activity.

    “Antipsychotic drugs do not improve the mitochondrial pathology observed in SZ, and some of these drugs inhibit complex I activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    With little ATP reserves, stressful situations or periods of decreased glucose availability could cause severe malfunctions, explaining known risk factors for affective disorders and schizophrenia.

    “Furthermore, with little ATP reserves (such a PCr) stressful situations or periods of decreased glucose availability could cause severe malfunctions, explaining known risk factors for affective disorders and SZ”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Brown and Derkits, 2010

      Not checked in the free run.

    • cites Brown and Yamamoto, 2003

      Not checked in the free run.

    • cites Kroll, 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rat liver, typical, but not atypical, antipsychotics inhibited complex I activity and facilitated activity of complex IV.

    “In rat liver, typical, but not atypical, antipsychotics inhibited complex I activity and facilitated activity of complex IV (Modica-Napolitano et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Modica-Napolitano et al., 2003

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In contrast to brain studies, complex I activity and expression of the 24- and 51-kDa iron-sulfur flavoprotein subunits were increased in platelets of schizophrenia patients, with no change in bipolar disorder patients.

    “In contrast to the various studies reporting a downregulation of mitochondrial genes in the brain, complex I activity and expression of the 24- and 51-kDa iron-sulfur flavoprotein subunits were increased in platelets of SZ patients, with no change in BPD patients (Ben-Shachar et al., 1999; Dror et al., 2002).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Ben-Shachar et al., 1999

      Not checked in the free run.

    • cites Dror et al., 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bipolar disorder patients exhibited a reduction and a left-right asymmetry in PCr levels that was not seen in controls, suggesting abnormalities in either the production or maintenance of high-energy phosphates.

    “BPD patients also exhibited a reduction and a left-right asymmetry in PCr levels that was not seen in controls, suggesting that BPD patients have abnormalities in either the production or maintenance of high-energy phosphates”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Deicken et al., 1995b

      Not checked in the free run.

    • cites Kato et al., 1994

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lithium increased the activity of electron transport chain complexes I, II and III in homogenates of the human prefrontal cortex, while a slight reduction was seen in complex IV activity at very high drug doses.

    “Lithium increased the activity of electron transport chain complexes I, II and III in homogenates of the human PFC, while a slight reduction was seen in complex IV activity at very high drug doses (Maurer et al., 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Maurer et al., 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both typical and atypical antipsychotic drugs increased complex IV activity in frontal cortex, but only atypical antipsychotic drugs increased complex IV activity in the hippocampus.

    “Both typical and atypical antipsychotic drugs increased complex IV activity in frontal cortex, but only atypical antipsychotic drugs increased complex IV activity in the hippocampus.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Prince et al., 1997a

      Not checked in the free run.

51 of 51

  • The paper relies on this without support.

    The primary disease-causing event in mitochondrial disorders is the mitochondrial DNA mutation.

    “as the primary disease-causing event in mitochondrial disorders is the mtDNA mutation.”

  • The paper relies on this without support.

    The brain depends exclusively on glycolysis and oxidative phosphorylation to create ATP.

    “Unlike most other tissues, the brain depends exclusively on glycolysis and OXPHOS to create ATP.”

  • The paper relies on this without support.

    Impairment of oxidative phosphorylation activity causes accumulation of lactate and unprocessed glucose.

    “Impairment of OXPHOS activity causes accumulation of lactate and unprocessed glucose (figure 2A).”

  • The paper relies on this without support.

    Rodent behavioral abnormalities such as increased startle response and altered circadian behavior are valid analogues of human psychiatric symptoms.

    “The results support the notion that mutations in mitochondria-related nuclear genes can reproduce behaviors seen in psychiatric illness.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Schizophrenia lactate finding contradicts the cited study's title

    Minor

    The text says the increased cerebrospinal-fluid lactate and glucose levels were not observed in schizophrenia patients in the same study. The cited study's title explicitly reports elevated cerebrospinal-fluid lactate in patients with schizophrenia, contradicting at least the lactate portion of that statement.

1 of 1

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1 of the 189 references couldn’t be matched to a known paper.

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Related

Authors
Clay, H. B., Daws, S., & Konradi, C.
Affiliations
Vanderbilt University (US)
Corresponding author
Konradi, Christine
ORCID
Venue
International Journal of Developmental Neuroscience
Publisher
Wiley
Published
2010-09-15
Volume
29
Issue
3
Pages
311-324
ISSN
  • 0736-5748 (ISSN-L)
  • 1873-474X
DOI
10.1016/j.ijdevneu.2010.08.007
PMC
PMC3010320
OpenAlex
W2069125243
Semantic Scholar
23e6000158294099c0ba4c2d466d5628d50d089b
Cited by
399
References
189
Citations by year
2026: 14 · 2025: 17 · 2024: 22 · 2023: 25 · 2022: 17 · 2021: 27 · 2020: 22 · 2019: 25 · 2018: 23 · 2017: 28 · 2016: 32 · 2015: 26 · 2014: 36 · 2013: 23 · 2012: 45
FWCI
2.38
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • International Journal of Developmental Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Mental Health (R21MH084131, R01MH067999, MH74000, R01MH074000, MH084131, MH67999)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords
mitochondrial dysfunction, bipolar disorder, schizophrenia, mitochondrial respiration, mitochondrial DNA mutations, mtDNA polymorphisms, DNA polymerase gamma, high-energy phosphates, brain pH, brain development, mood disorders, cognitive decline, psychiatric medication, energy metabolism
MeSH terms
Animals, Bipolar Disorder, Brain, Calcium, DNA Damage, Energy Metabolism, Humans, Mitochondria, Mutation, Oxidative Phosphorylation, Phenotype, Polymorphism, Genetic, RNA, Messenger, Schizophrenia, Antipsychotic Agents, Apoptosis, Oxidative Stress, Mitochondrial Diseases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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