Primary mitochondrial diseases increase susceptibility to bipolar affective disorder

Colasanti, Alessandro; Bugiardini, Enrico; Amawi, Sami Omar; Poole, Olivia V.; Skorupinska, Iwona; Skorupinska, Mariola; Germain, Louise; Kozyra, Damian; Holmes, Sarah; James, Natalie; Woodward, Cathy E.; Quinlivan, R.; Young, Allan H.; Hanna, Michael G.; Pitceathly, Robert D S

doi:10.1136/jnnp-2020-323632

Cited by 19 publications

(11 citation statements)

References 6 publications

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“…Mitochondrial dysfunction has been associated with psychiatric disorders such as BD [ 8 , 38 ]. Evidence of mitochondrial alterations has been reported in BD patients [ 18 , 21 , 22 , 39 ] and, in turn, a high prevalence of affective syndromes, particularly BD, have been shown in adults with primary mitochondrial diseases [ 12 ]. This study provides evidence supporting that alterations in mitochondria occur in early phases of BD and that is evident in non-neuronal peripheral cells.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial Alterations in Fibroblasts of Early Stage Bipolar Disorder Patients

Marques

Resende²,

Silva³

et al. 2021

Biomedicines

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This study aims to evaluate whether mitochondrial changes occur in the early stages of bipolar disorder (BD). Using fibroblasts derived from BD patients and matched controls, the levels of proteins involved in mitochondrial biogenesis and dynamics (fission and fusion) were evaluated by Western Blot analysis. Mitochondrial membrane potential (MMP) was studied using the fluorescent probe TMRE. Mitochondrial morphology was analyzed with the probe Mitotracker Green and mitophagy was evaluated by quantifying the co-localization of HSP60 (mitochondria marker) and LC3B (autophagosome marker) by immunofluorescence. Furthermore, the activity of the mitochondrial respiratory chain and the glycolytic capacity of controls and BD patients-derived cells were also studied using the Seahorse technology. BD patient-derived fibroblasts exhibit fragmented mitochondria concomitantly with changes in mitochondrial dynamics and biogenesis in comparison with controls. Moreover, a decrease in the MMP and increased mitophagy was observed in fibroblasts obtained from BD patients when compared with control cells. Impaired energetic metabolism due to inhibition of the mitochondrial electron transport chain (ETC) and subsequent ATP depletion, associated with glycolysis stimulation, was also a feature of BD fibroblasts. Overall, these results support the fact that mitochondrial disturbance is an early event implicated in BD pathophysiology that might trigger neuronal changes and modification of brain circuitry.

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Section: Discussionmentioning

confidence: 99%

“…Much evidence from genetic, functional and neuroimaging studies, suggesting that mitochondrial dysfunction may play a key role in BD pathophysiology, has been published in the last two decades [ 8 , 11 ]. Interestingly, primary mitochondrial diseases increase susceptibility to BD [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Alterations in Fibroblasts of Early Stage Bipolar Disorder Patients

Marques

Resende²,

Silva³

et al. 2021

Biomedicines

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“…This overlap is not surprising given that patients are frequently encephalopathic during the acute presentation of stroke-like episodes.t 36,37 . We also identified a region of suggestive linkage to psychiatric involvement, a feature frequently seen in combination with encephalopathy 12 but also a feature of the wider group of primary mitochondrial diseases 38 . In contrast, no linkage regions were identified for cerebellar ataxia, migraine, diabetes mellitus, hearing impairment or CPEO, showing that not every disease phenotype is influenced by the nuclear genome in the same manner; any nuclear factors involved in the development of these phenotypes may be more polygenic in nature.…”

Section: Discussionmentioning

confidence: 81%

Defining the nuclear genetic architecture of a common maternally inherited mitochondrial disorder

Boggan

Franklin

et al. 2022

Preprint

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Maternally inherited mitochondrial diseases are caused by pathogenic mitochondrial (mt)DNA variants. Affecting individuals at any age, they are often multi-systemic and manifest extreme clinical variability. We have very little understanding of the cause of this heterogeneity, which makes disease diagnosis and prognosis exceptionally challenging. This is clearly demonstrated by disease caused by m.3243A>G, the most common pathogenic mtDNA variant. m.3243A>G can cause a severe syndrome characterised by mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS), but individuals who carry m.3243A>G may be asymptomatic or present with any number of a range of phenotypes. There is strong evidence for the presence of nuclear factors that modify phenotype; we set out to characterise the nature of this nuclear involvement using genetic linkage analysis. We assembled a multi-centre cohort of well-characterised patients and their maternal relatives, comprising 76 pedigrees, and characterised the nuclear genetic landscape of m.3243A>G-related disease phenotypes using non-parametric genetic linkage analysis. We considered eight of the most common m.3243A>G-related phenotypes, accounted for known risk factors using logistic regression, and determined empirical significance using simulation to identify regions of the nuclear genome most likely to contain disease modifying variants. We identified significant genetic linkage to encephalopathy on chromosome 7q22, and suggestive regions for encephalopathy, stroke-like episodes and psychiatric involvement on chromosomes 1, 5, 6, 11 and 13. These findings suggest that these neurological features are likely to be influenced by a small number of nuclear factors with a relatively large effect size. In contrast, no linkage regions were identified for cerebellar ataxia, migraine, diabetes mellitus, hearing impairment or chronic progressive external ophthalmoplegia. The genetic architecture of the nuclear factors influencing disease related to m.3243A>G differs between phenotypes. Severe and cardinal neurological features of MELAS are likely to be strongly influenced by a small number of nuclear genes, whereas the nuclear influence over other phenotypic presentations is more likely to be polygenic and complex in nature, composed of a larger number of factors that each exert a small effect. These results will inform strategies for future studies to identify the genes and pathways that influence clinical heterogeneity in m.3243A>G-related disease, with the ultimate aim of better understanding disease development and progression.

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“…In addition to neurogenesis, associations between reduced hippocampal volume and cognitive impairment in bipolar disorder may be mediated by inflammation or neuronal toxicity, 66 although longitudinal studies are needed to ascertain temporal associations between these putatively related phenomena. Oxidative stress may also implicate mitochondrial, 67 HPA axis, 68 monoamine 26 and/or white matter 69 , 70 dysfunctions, all of which have been linked with bipolar disorder and cognitive difficulties. Additionally, genetic interactions may provide additional support for some of the above relationships, e.g.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory biomarkers and cognitive functioning in individuals with euthymic bipolar disorder: exploratory study

et al. 2021

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Background Neurobiological research frequently implicates inflammatory and neurogenic components with core aspects of bipolar disorder. Even in periods of symptom remission (euthymia), individuals with bipolar disorder experience cognitive impairments, which are increasingly being proposed as an outcome for interventions; identifying biomarkers associated with cognitive impairment in people with bipolar disorder could advance progress in this therapeutic field through identifying biological treatment targets. Aims We aimed to identify proteomic biomarker correlates of cognitive impairment in individuals with euthymic bipolar disorder. Method Forty-four adults with a bipolar disorder diagnosis in euthymia underwent a battery of cognitive assessments and provided blood for biomarkers. We examined a comprehensive panel of inflammatory and trophic proteins as putative cross-sectional predictors of cognition, conceptualised according to recommended definitions of clinically significant cognitive impairment (binary construct) and global cognitive performance (continuous measure). Results A total of 48% of the sample met the criteria for cognitive impairment. Adjusting for potentially important covariates, regression analyses identified lower levels of three proteins as significantly and independently associated with cognitive deficits, according to both binary and continuous definitions (interleukin-7, vascular endothelial growth factor C and placental growth factor), and one positively correlated with (continuous) global cognitive performance (basic fibroblast growth factor). Conclusions This study identifies four candidate markers of cognitive impairment in bipolar disorder, none of which have been previously compared with cognitive function in participants with bipolar disorder. Pending replication in larger samples and support from longitudinal studies, these markers could have implications for treating cognitive dysfunction in this patient population.

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Primary mitochondrial diseases increase susceptibility to bipolar affective disorder

Cited by 19 publications

References 6 publications

Mitochondrial Alterations in Fibroblasts of Early Stage Bipolar Disorder Patients

Mitochondrial Alterations in Fibroblasts of Early Stage Bipolar Disorder Patients

Defining the nuclear genetic architecture of a common maternally inherited mitochondrial disorder

Inflammatory biomarkers and cognitive functioning in individuals with euthymic bipolar disorder: exploratory study

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