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, 7 (5), e1111

Perturbations in the Apoptotic Pathway and Mitochondrial Network Dynamics in Peripheral Blood Mononuclear Cells From Bipolar Disorder Patients

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Perturbations in the Apoptotic Pathway and Mitochondrial Network Dynamics in Peripheral Blood Mononuclear Cells From Bipolar Disorder Patients

G Scaini et al. Transl Psychiatry.

Abstract

Bipolar disorder (BD) is a severe psychiatric disorder characterized by phasic changes of mood and can be associated with progressive structural brain change and cognitive decline. The numbers and sizes of glia and neurons are reduced in several brain areas, suggesting the involvement of apoptosis in the pathophysiology of BD. Because the changes in mitochondrial dynamics are closely related with the early process of apoptosis and the specific processes of apoptosis and mitochondrial dynamics in BD have not been fully elucidated, we measured the apoptotic pathway and the expression of mitochondrial fission/fusion proteins from BD patients and healthy controls. We recruited 16 patients with BD type I and sixteen well-matched healthy controls and investigated protein levels of several pro-apoptotic and anti-apoptotic factors, as well as the expression of mitochondrial fission/fusion proteins in peripheral blood mononuclear cells (PBMCs). Our results showed that the levels of the anti-apoptotic proteins Bcl-xL, survivin and Bcl-xL/Bak dimer were significantly decreased, while active caspase-3 protein levels were significantly increased in PBMCs from BD patients. Moreover, we observed the downregulation of the mitochondrial fusion-related proteins Mfn2 and Opa1 and the upregulation of the fission protein Fis1 in PBMCs from BD patients, both in terms of gene expression and protein levels. We also showed a significantly decrease in the citrate synthase activity. Finally, we found a positive correlation between Mfn2 and Opa1 with mitochondrial content markers, as well as a negative correlation between mitochondrial fission/fusion proteins and apoptotic markers. Overall, data reported here are consistent with the working hypothesis that apoptosis may contribute to cellular dysfunction, brain volume loss and progressive cognitive in BD. Moreover, we show an important relationship between mitochondrial dynamics and the cell death pathway activation in BD patients, supporting the link between mitochondrial dysfunction and the pathophysiology of BD.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Alteration of anti- and pro-apoptotic proteins in peripheral blood mononuclear cells (PBMCs) from healthy controls and patients with Bipolar Disorder type I (BD-I). (a) Protein levels of Bcl-xL, (b) Protein levels of Bcl-xL/Bak dimer, (c) Protein levels of survivin and (d) Protein levels of active caspase-3. Data were presented as median and interquartile range (IQR). Differences between 2 groups were compared using the Mann–Whitney U-test. Different from the control group; *P<0.05.
Figure 2
Figure 2
Alteration of mitochondrial fusion proteins in peripheral blood mononuclear cells (PBMCs) from healthy controls and patients with Bipolar Disorder type I (BD-I). (a) Relative mRNA expression of Mfn1, (b) Protein levels of Mfn1 (c) Relative mRNA expression of Mfn2, (d) Protein levels of Mfn2, (e) Relative mRNA expression of Opa1, (f) Protein levels of Opa1. Data were presented as median and interquartile range (IQR). Differences between 2 groups were compared using the Mann–Whitney U-test. Different from the control group; *P<0.05.
Figure 3
Figure 3
Alteration of mitochondrial fission proteins in peripheral blood mononuclear cells (PBMCs) from healthy controls and patients with Bipolar Disorder type I (BD-I). (a) Relative mRNA expression of Fis1, (b) Protein levels of Fis1, (c) Relative mRNA expression of Drp1, (d) Protein levels of Drp1. Data were presented as median and interquartile range (IQR). Differences between 2 groups were compared using the Mann–Whitney U-test. Different from the control group; *P<0.05.
Figure 4
Figure 4
Mitochondrial mass in in peripheral blood mononuclear cells (PBMCs) from healthy controls and patients with Bipolar Disorder type I (BD-I). (a) Distribution of relative mtDNA copy number. (b) Citrate synthase activity. (c) Correlation coefficient (Pearson's correlation coefficient) between citrate synthase activity and protein levels of Mfn2. (d) Correlation coefficient (Spearman's rank correlation test) between citrate synthase activity and protein levels of Opa1. Data were presented as median and interquartile range (IQR). Differences between 2 groups were compared using the Mann–Whitney U-test. Different from the control group; *P<0.05.
Figure 5
Figure 5
Correlation coefficient of active caspase-3, Bcl-xL and Bcl-xL/Bak dimer protein levels with Mfn2, Opa1 and Fis1 in peripheral blood mononuclear cells (PBMCs) from healthy controls and patients with Bipolar Disorder type I (BD-I). Results were assessed using the Spearman's rank correlation test.
Figure 6
Figure 6
Correlation coefficient of Young Mania Rating Scale (YMRS) score (a), Montgomery-Asberg Depression Scale (MADRS) score (b), number of manic episodes (c), Functional Assessment Screening Tool (FAST) scale (d) and Global Assessment of Functioning (GAF) scale (e) with Mfn2 protein levels in peripheral blood mononuclear cells (PBMCs) from healthy controls and patients with Bipolar Disorder type I (BD-I). Results were assessed using the Spearman's rank correlation test.
Figure 7
Figure 7
Schematic diagram illustrating the disruption of the balance between mitochondrial fusion and fission in bipolar disorder (BD) patients, and also the modulation of Bcl-2 family. This imbalance in mitochondrial fission and fusion towards fission causes mitochondrial fragmentation and may directly drive the cell into apoptosis, leading to the release of pro-apoptotic proteins, cristae remodeling, and activation of caspase-3. Moreover, members of the Bcl-2 family may participate in the regulation of mitochondrial fission/fusion dynamics in BD patients.

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