Nod-like receptor pyrin containing 3 (NLRP3) in the post-mortem frontal cortex from patients with bipolar disorder: A potential mediator between mitochondria and immune-activation

Kim, Helena Kyunghee; Andreazza, Ana Cristina; Elmi, Nika; Chen, Wenjun; Young, L. Trevor

doi:10.1016/j.jpsychires.2015.10.015

Cited by 110 publications

(76 citation statements)

References 77 publications

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“…Prior studies of the frontal cortex of subjects with BD [41] and SZ [42] have reported reductions in complex I activity. These reductions might be the result of an overrepresentation of subjects with chronic antipsychotic medication that reduces complex I activity.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

Rollins¹,

Morgan²,

Hjelm³

et al. 2017

Complex Psychiatry

View full text Add to dashboard Cite

show abstract

“…Moreover, the proinflammatory status decreases the expression of the brain-derived neurotrophic factor (BDNF) and induces OS and nitrosative stress, thus contributing to the neural loss [39]. The link between inflammation and OS has been recently related to the nod-like receptor pyrin domain-containing 3 (NLRP3), an inflammatory redox sensor whose activation has been associated with the production of ROS [41]. In addition, the expression of nitric oxide (NO), typical of the inflammatory states, can facilitate the occurrence of OS, thus leading to cellular damage, particularly in the brain.…”

Section: Methodsmentioning

confidence: 99%

“…A dysfunction in the mitochondria complexes has been demonstrated in bipolar patients [45]. More specifically, the mitochondrial complex I subunits seem to be particularly involved [41, 45]. In fact, a downregulation of this system, and the consequential overproduction of ROS, has been variously reported [41, 46].…”

Section: Methodsmentioning

confidence: 99%

“…More specifically, the mitochondrial complex I subunits seem to be particularly involved [41, 45]. In fact, a downregulation of this system, and the consequential overproduction of ROS, has been variously reported [41, 46]. In addition, an impaired endoplasmic reticulum (ER) stress response, negatively affecting neurodevelopment and neuroplasticity (it is worth pondering over that ER is involved in the regulation of protein folding), has been identified as one of the multiple biological bases of BD [47].…”

Section: Methodsmentioning

confidence: 99%

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Gsk3 Signalling and Redox Status in Bipolar Disorder: Evidence from Lithium Efficacy

Luca

Calandra

Luca

2016

Oxidative Medicine and Cellular Longevity

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Objective. To discuss the link between glycogen synthase kinase-3 (GSK3) and the main biological alterations demonstrated in bipolar disorder (BD), with special attention to the redox status and the evidence supporting the efficacy of lithium (a GSK3 inhibitor) in the treatment of BD. Methods. A literature research on the discussed topics, using Pubmed and Google Scholar, has been conducted. Moreover, a manual selection of interesting references from the identified articles has been performed. Results. The main biological alterations of BD, pertaining to inflammation, oxidative stress, membrane ion channels, and circadian system, seem to be intertwined. The dysfunction of the GSK3 signalling pathway is involved in all the aforementioned “biological causes” of BD. In a complex scenario, it can be seen as the common denominator linking them all. Lithium inhibition of GSK3 could, at least in part, explain its positive effect on these biological dysfunctions and its superiority in terms of clinical efficacy. Conclusions. Deepening the knowledge on the molecular bases of BD is fundamental to identifying the biochemical pathways that must be targeted in order to provide patients with increasingly effective therapeutic tools against an invalidating disorder such as BD.

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“…The most replicated findings that show consistency with genome-wide association studies (GWAS), brain-imaging and post-mortem brain expression include abnormalities in endoplasmic reticulum (ER)-related stress responses, mitochondrial function and Ca 2+ signaling, which are often reversed in vitro with lithium. Furthermore, patient-derived cellular models also support that alterations in microRNAs (miRNAs), glia and immune cell signaling, cytoskeleton as well as oxidative stress, inflammasome activation, autophagy and apoptosis play a relevant role in BD pathophysiology [8,[19][20][21][22][23][24][25][26][27][28][29]. …”

mentioning

confidence: 99%

The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

Pereira¹,

Resende²,

Morais³

et al. 2017

IJCNMH

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Mental health problems constitute the largest single source of world economic burden, with an estimated global cost greater than cardiovascular disease, cancer or diabetes individually. In the European Union mental disorders affect millions of people and these numbers are expected to rise as result of Europe's ageing population. Given the biological causes of many of these disorders, most studies focus on their molecular basis. Bipolar disorder (BD) is characterized by mood swings between depression and mania resulting in cognitive and functional impairments that require lifetime treatment. Recurrent mood episodes, residual symptoms, functional impairment, psychosocial disability with high rates of divorce, unemployment, drug abuse and suicide attempting, and significant medical comorbidities such as metabolic and cardiovascular diseases cannot be efficiently controlled even with proper use of current treatments. Moreover, delayed diagnosis/misdiagnosis is frequent because reliable biomarkers are absent. Therefore, a better understanding of BD pathophysiology is a prerequisite for the design of new drugs and their implementation in clinical practice as well as to develop biomarkers for a more accurate and earlier diagnosis and/or evaluation of therapeutic response. This review summarises the association between decreased cellular resilience towards stress and BD. Since the key stress-response mediator Mitochondria-Associated Membranes (MAMs) modulate several BD relevant processes such as mitochondrial dysfunction and oxidative stress, Ca 2+ deregulation and cytoskeleton abnormalities, endoplasmic reticulum stress responses, loss of proteostasis and inflammasome activation, we propose the "MAM hypothesis" for BD pathophysiology. Targeting MAM-associated signaling pathways can be a promising investigation avenue to identify novel therapeutic strategies.Keywords: Bipolar disorder, Endoplasmic reticulum, Mitochondria, Mitochondria-associated membranes, Cellular resilience, Cellular stress, Plasticity. Bipolar DisorderBD is a chronic psychiatric illness with a remitting course, affecting 2.4% of the general population [1], characterized by mood swings between manic and depressive states that result in cognitive and functional impairments, high health care costs and premature mortality [2,3]. BD is the sixth leading cause of disability worldwide responsible for loss of more disability-adjusted life-years than all forms of cancer and major neurological conditions [4]. BD is associated with greatly impaired quality of life and increased physical health burden [5]. Moreover, BD patients tend to have high rates of divorce, unemployment, drug abuse and crime as consequence of impaired social cognition, and its impact on patients can be devastating, with approximately 23% of patients with BD reported having suicide attempts [6]. Moreover, individuals with BD diagnosis have a high risk of medical comorbidities such as metabolic (diabetes, obesity and metabolic syndrome) and cardiovascular disorders [7].Current knowl...

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Nod-like receptor pyrin containing 3 (NLRP3) in the post-mortem frontal cortex from patients with bipolar disorder: A potential mediator between mitochondria and immune-activation

Cited by 110 publications

References 77 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

Gsk3 Signalling and Redox Status in Bipolar Disorder: Evidence from Lithium Efficacy

The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

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