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Mitochondrial health index correlates with plasma circulating cell-free mitochondrial DNA in bipolar disorder

Molecular Psychiatry volume 28, pages 4622–4631 (2023)Cite this article

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Abstract

Although mitochondrial dysfunction is known to play an essential role in the pathophysiology of bipolar disorder (BD), there is a glaring gap in our understanding of how mitochondrial dysfunction can modulate clinical phenotypes. An emerging paradigm suggests mitochondria play an important non-energetic role in adaptation to stress, impacting cellular resilience and acting as a source of systemic allostatic load. Known as mitochondrial allostatic load, this (phenomenon) occurs when mitochondria are unable to recalibrate and maintain cell homeostasis. This study aimed to evaluate the composite mitochondrial health index (MHI) in BD subjects and non-psychiatry controls. We will also explore whether lower MIH will be related to higher cell-free mtDNA (ccf-mtDNA) levels and poor clinical outcomes. In this study, 14 BD-I patients and 16 age- and sex-matched non-psychiatry controls were enrolled. Peripheral blood mononuclear cells (PBMCs) were used to measure the enzymatic activities of citrate synthase and complexes I, II, and IV and mtDNA copy number. Ccf-mtDNA was evaluated by qPCR in plasma. Mitochondrial quality control (MQC) proteins were evaluated by western blotting. After adjusting for confounding variables, such as age, sex, body mass index (BMI), and smoking status, patients with BD presented lower MHI compared to non-psychiatry controls, as well as higher ccf-mtDNA levels that negatively correlated with MHI. Because the MQC network is essential to maintain mitochondrial health, MHI and ccf-mtDNA were also examined in relation to several MQC-related proteins, such as Fis-1, Opa-1, and LC3. Our results showed that MHI correlated negatively with Fis-1 and positively with Opa-1 and LC3. Accordingly, ccf-mtDNA had a positive correlation with Fis-1 and a negative correlation with Opa-1 and LC3. Furthermore, we found a noteworthy inverse correlation between illness severity and MHI, with lower MHI and higher ccf-mtDNA levels in subjects with a longer illness duration, worse functional status, and higher depressive symptoms. Our findings indicate that mitochondrial allostatic load contributes to BD, suggesting mitochondria represent a potential biological intersection point that could contribute to impaired cellular resilience and increased vulnerability to stress and mood episodes. Ultimately, by linking mitochondrial dysfunction to disease progression and poor outcomes, we might be able to build a predictive marker that explains how mitochondrial function and its regulation contribute to BD development and that may eventually serve as a treatment guide for both old and new therapeutic targets.

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Fig. 1: Mitochondrial Health Index in Bipolar Disorder Patients.
Fig. 2: Plasma Circulating Cell-free Mitochondrial DNA in Bipolar Disorder Patients.
Fig. 3: Mitochondrial health index and circulating cell-free mitochondrial DNA are associated with symptom severity and functional status.

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Funding

Funding

The research funding support from the University of Texas Health Science Center at Houston, the Louis A. Faillace, MD Endowment Funds, and the Translational Psychiatry Program to GS, GRF, and JQ are acknowledged. The 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, the John S. Dunn Foundation, and the 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 the University of Southern Santa Catarina (UNESC). GRF is funded by the National Institute of Mental Health (5K01MH121580) and the Baszucki Research Foundation.

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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

    Rafaela C. Cordeiro, Camila N. C. Lima, Gabriel R. Fries, João Quevedo & Giselli Scaini

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

    Gabriel R. Fries, João Quevedo & Giselli Scaini

  3. 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

    Gabriel R. Fries, Giovana Zunta-Soares, Jair C. Soares, João Quevedo & Giselli Scaini

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

    Gabriel R. Fries, João Quevedo & Giselli Scaini

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  1. Rafaela C. Cordeiro
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Contributions

GS conceived and designed the study hypothesis. RCC and GS analyzed and interpreted the data, conducted literature searches, prepared tables/figures, and co-wrote the first draft of the manuscript. CNCL assisted with the biochemical assessments, and GRF assisted with the statistical analysis and data interpretation. JQ, GZS, and JCS were involved in subject recruitment, data collection, and clinical data interpretation. All authors reviewed the manuscript for intellectual content and approved the final version of the manuscript.

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Correspondence to Giselli Scaini.

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Cordeiro, R.C., Lima, C.N.C., Fries, G.R. et al. Mitochondrial health index correlates with plasma circulating cell-free mitochondrial DNA in bipolar disorder. Mol Psychiatry 28, 4622–4631 (2023). https://doi.org/10.1038/s41380-023-02249-y

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