Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer's disease

Krishnan, Kim J.; Ratnaike, Thiloka; Gruyter, Heidi L.M. De; Jaros, Evelyn; Turnbull, Doug M.

doi:10.1016/j.neurobiolaging.2011.08.009

Cited by 85 publications

(62 citation statements)

References 21 publications

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“…From a genetic perspective, there is currently insufficient evidence to support the involvement of particular mtDNA polymorphisms with any psychiatric disorder. Despite some initial promising findings, overall it appears that mitochondrial deletions are not associated with psychiatric illness, and low level heteroplasmy for mtDNA deletions identified using LR-PCR may be attributable to aging [Elstner et al, 2011;Krishnan et al, 2011]. Similarly, two studies have failed to find significant mtDNA copy number variations in bipolar disorder, schizophrenia, and major depressive disorder.…”

Section: Summary and Future Directionsmentioning

confidence: 95%

The mitochondrial genome and psychiatric illness

Anglin

Mazurek

Tarnopolsky

et al. 2012

American J of Med Genetics Pt B

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Psychiatric disorders are a leading cause of morbidity and mortality, yet their underlying pathophysiology remains unclear. Searches for a genetic cause of bipolar disorder, schizophrenia, and major depressive disorder have yielded inconclusive results. There is increasing interest in the possibility that defects in the mitochondrial genome may play an important role in psychiatric illness. We undertook a review of the literature investigating mitochondria and adult psychiatric disorders. MEDLINE, PsycINFO, and EMBASE were searched from their inception through September 2011, and the reference lists of identified articles were reviewed for additional studies. While multiple lines of evidence, including clinical, genetic, ultrastructural, and biochemical studies, support the involvement of mitochondria in the pathophysiology of psychiatric illness, many studies have methodological limitations and their findings have not been replicated. Clinical studies suggest that psychiatric features can be prominent, and the presenting features of mitochondrial disorders. There is limited but inconsistent evidence for the involvement of mitochondrial DNA haplogroups and mitochondria-related nuclear gene polymorphisms, and for mitochondrial ultrastructural and biochemical abnormalities in psychiatric illness. The current literature suggests that mitochondrial dysfunction and mitochondrial genetic variations may play an important role in psychiatric disorders, but additional methodologically rigorous and adequately powered studies are needed before definitive conclusions can be drawn.

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Section: Summary and Future Directionsmentioning

confidence: 95%

The mitochondrial genome and psychiatric illness

Anglin

Mazurek

Tarnopolsky

et al. 2012

American J of Med Genetics Pt B

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“…We performed dual histochemistry to identify and quantify deficiency of COX alongside SDH-positive cells within the PPN, using a previously described method. 51 …”

Section: Cox-sdh Histochemistrymentioning

confidence: 99%

Mitochondrial Abnormality Associates with Type-Specific Neuronal Loss and Cell Morphology Changes in the Pedunculopontine Nucleus in Parkinson Disease

Pienaar

Elson

Racca

et al. 2013

The American Journal of Pathology

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Cholinergic neuronal loss in the pedunculopontine nucleus (PPN) associates with abnormal functions, including certain motor and nonmotor symptoms. This realization has led to low-frequency stimulation of the PPN for treating patients with Parkinson disease (PD) who are refractory to other treatment modalities. However, the molecular mechanisms underlying PPN neuronal loss and the therapeutic substrate for the clinical benefits following PPN stimulation remain poorly characterized, hampering progress toward designing more efficient therapies aimed at restoring the PPN's normal functions during progressive parkinsonism. Here, we investigated postmortem pathological changes in the PPN of PD cases. Our study detected a loss of neurons producing gamma-aminobutyric acid (GABA) as their output and glycinergic neurons, along with the pronounced loss of cholinergic neurons. These losses were accompanied by altered somatic cell size that affected the remaining neurons of all neuronal subtypes studied here. Because studies showed that mitochondrial dysfunction exists in sporadic PD and in PD animal models, we investigated whether altered mitochondrial composition exists in the PPN. A significant up-regulation of several mitochondrial proteins was seen in GABAergic and glycinergic neurons; however, cholinergic neurons indicated down-regulation of the same proteins. Our findings suggest an imbalance in the activity of key neuronal subgroups of the PPN in PD, potentially because of abnormal inhibitory activity and altered cholinergic outflow.

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“…Large deletions of the mtDNA genome can potentially cause mitochondria dysfunction due to decreased energy production because of decreased complexes I-V, or generation of more reactive oxygen species leading to more oxidative stress. 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].…”

Section: Introductionmentioning

confidence: 99%

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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Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer's disease

Cited by 85 publications

References 21 publications

The mitochondrial genome and psychiatric illness

The mitochondrial genome and psychiatric illness

Mitochondrial Abnormality Associates with Type-Specific Neuronal Loss and Cell Morphology Changes in the Pedunculopontine Nucleus in Parkinson Disease

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

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