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TSPO upregulation in bipolar disorder and concomitant downregulation of mitophagic proteins and NLRP3 inflammasome activation

Neuropsychopharmacology (2018) | Download Citation

Abstract

Bipolar disorder (BD) is a chronic, debilitating illness with a global prevalence of up to 4.8%. The importance of understanding how dysfunctional mitochondria and mitophagy contribute to cell survival and death in BD is becoming increasingly apparent. Therefore, the purpose of this study was to evaluate the mitophagic pathway and NLRP3 inflammasome activation in peripheral blood mononuclear cells (PBMCs) of patients with BD and healthy individuals. Since 18-kDa translocator protein (TSPO) plays an important role in regulating mitochondrial function and since TSPO itself impairs cellular mitophagy, we also investigated the changes in the TSPO-related pathway. Our results showed that patients with BD had lower levels of Parkin, p62/SQSTM1 and LC3A and an upregulation of TSPO pathway proteins (TSPO and VDAC), both in terms of mRNA and protein levels. Additionally, we found a negative correlation between mitophagy-related proteins and TSPO levels, while VDAC correlated negatively with p62/SQSTM1 and LC3 protein levels. Moreover, we found that the gene expression levels of the NLRP3-related proteins NLRP3, ASC, and pro-casp1 were upregulated in BD patients, followed by an increase in caspase-1 activity as well as IL-1β and IL-18 levels. As expected, there was a strong positive correlation between NLRP3-related inflammasome activation and TSPO-related proteins. The data reported here suggest that TSPO-VDAC complex upregulation in BD patients, the simultaneous downregulation of mitophagic proteins and NLRP3 inflammasome activation could lead to an accumulation of dysfunctional mitochondria, resulting in inflammation and apoptosis. In summary, the findings of this study provide novel evidence that mitochondrial dysfunction measured in peripheral blood is associated with BD.

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Funding and disclosure

This study was supported in part by grants from the Pat Rutherford, Jr., Endowed Chair in Psychiatry (JCS), the John S. Dunn Foundation (JCS), and the NIMH (R01MH085667-01 A1) (JCS). The Center of Excellence on Mood Disorders and Translational Psychiatry Program (USA) is funded by the Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Medical School at Houston. The Laboratory of Neurosciences (Brazil) is one of the centers of the National Institute for Molecular Medicine (INCT-MM) and one of the members of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). Giselli Scaini thanks the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for a postdoctoral fellowship (205680/2014-3). The authors declare no competing interests.

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  1. These authors contributed equally: Giselli Scaini, Tatiana Barichello

Affiliations

  1. Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    • Giselli Scaini
    • , Tatiana Barichello
    • , Gabriel R. Fries
    • , Elizabeth A. Kennon
    • , Taylor Andrews
    •  & João Quevedo
  2. Experimental Pathophysiology Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil

    • Tatiana Barichello
  3. Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    • Bobby R. Nix
    • , Giovana Zunta-Soares
    • , Jair C. Soares
    •  & João Quevedo
  4. Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil

    • Samira S. Valvassori
    •  & João Quevedo
  5. Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA

    • Jair C. Soares
    •  & João Quevedo

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Correspondence to João Quevedo.

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https://doi.org/10.1038/s41386-018-0293-4