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Dysregulation of mitochondrial dynamics, mitophagy and apoptosis in major depressive disorder: Does inflammation play a role?

Molecular Psychiatry volume 27, pages 1095–1102 (2022)Cite this article

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Abstract

Recent studies have suggested that mitochondrial dysfunction and dysregulated neuroinflammatory pathways are involved in the pathophysiology of major depressive disorder (MDD). Here, we aimed to assess the differences in markers of mitochondrial dynamics, mitophagy, general autophagy, and apoptosis in peripheral blood mononuclear cells (PBMCs) of MDD patients (n = 77) and healthy controls (HCs, n = 24). Moreover, we studied inflammation engagement as a moderator of mitochondria dysfunctions on the severity of depressive symptoms. We found increased levels of Mfn-2 (p < 0.001), short Opa-1 (S-Opa-1) (p < 0.001) and Fis-1 (p < 0.001) in MDD patients, suggesting an increase in the mitochondrial fragmentation. We also found that MDD patients had higher levels of Pink-1 (p < 0.001), p62/SQSTM1 (p < 0.001), LC3B (p = 0.002), and caspase-3 active (p = 0.001), and lower levels of parkin (p < 0.001) compared with HCs. Moreover, we showed that that MDD patients with higher CRP levels had higher levels of Mfn-2 (p = 0.001) and LC3B (p = 0.002) when compared with MDD patients with low CRP. Another notable finding was that the severity of depressive symptoms in MDD is associated with changes in protein levels in pathways related to mitochondrial dynamics and mitophagy, and can be dependent on the inflammatory status. Overall, our study demonstrated that a disruption in the mitochondrial dynamics network could initiate a cascade of abnormal changes relevant to the critical pathological changes during the course of MDD and lead to poor outcomes.

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Fig. 1: Levels of proteins involved in mitochondrial dynamics and mitophagy in patients with major depressive disorder.
Fig. 2: Levels of mitochondrial proteins in patients with major depressive stratified by C-Reactive Protein.
Fig. 3: Levels of anti- and pro-apoptotic proteins in patients with Major Depressive Disorder.
Fig. 4: Simple slopes plots for the moderation of CRP on the relationship between mitochondrial and apoptotic markers with QIDS-C.

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Funding

The T-RAD study is generously supported by The Hersh Foundation, Jordan E. Harris Foundation, W. W. Caruth, Jr. Fund, Evelyn Rose, M2G Ventures, and support for the use of REDCap (CTSA NIH Grant UL1TR001105). The research funding support from the University of Texas health science centre at Houston, the Louis A. Faillace, MD Endowment Funds and the Translational Psychiatry Program to GS and JQ are acknowledged. Translational Psychiatry Program (USA) is funded by the Department of Psychiatry and Behavioral Sciences, McGovern Medical School at UTHealth and Linda Gail Behavioral Health Research Fund. Center of Excellence on Mood Disorders (USA) is funded by the Pat Rutherford Jr Chair in Psychiatry, John S. Dunn Foundation and Anne and Don Fizer Foundation Endowment for Depression Research. Translational Psychiatry Laboratory (Brazil) is funded by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC), Instituto Cérebro e Mente and University of Southern Santa Catarina (UNESC).

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Authors and Affiliations

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

    Giselli Scaini & João Quevedo

  2. Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA

    Giselli Scaini & João Quevedo

  3. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Brittany L. Mason & Manish K. Jha

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

    Alexandre P. Diaz, Jair C. Soares & João Quevedo

  5. Peter O’Donnell Brain Institute, Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA

    Madhukar H. Trivedi

  6. Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil

    João Quevedo

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Contributions

GS, BLM, MHT, and JQ contribute to conception and design, analysis and interpretation of clinical data, and final approval of the version to be published. GS performed biochemical assessments, data analysis and wrote the paper with input from all authors. APD assisted with statistical analysis and manuscript preparation. MKJ and JCS revised the paper critically for relevant intellectual content.

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Correspondence to Giselli Scaini.

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Scaini, G., Mason, B.L., Diaz, A.P. et al. Dysregulation of mitochondrial dynamics, mitophagy and apoptosis in major depressive disorder: Does inflammation play a role?. Mol Psychiatry 27, 1095–1102 (2022). https://doi.org/10.1038/s41380-021-01312-w

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