Mitochondrial Alterations in Fibroblasts of Early Stage Bipolar Disorder Patients.

Ana P Marques,Brigite Wildenberg,António Macedo,Mariana Batista,Daniela Pereira,Cláudia Pais,Sofia Morais,Cláudia F Pereira,Joana B Melo,Nuno Madeira,Diana F Silva,Rosa Resende

doi:10.3390/biomedicines9050522

Ana P Marques, Brigite Wildenberg + Show 10 more

Open Access

https://doi.org/10.3390/biomedicines9050522

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Abstract

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.

Highlights

Bipolar disorder (BD) is a chronic and debilitating mental disorder that affects about 45 million people worldwide [1] and is characterized by frequent changes in mood, between mania/hypomania and depression, expressed as recurrent changes in energy levels and behavior [2]
Several studies suggest that bipolar disorder (BD) may be associated with alterations in mitochondrial function, so mitochondrial morphology changes were evaluated by immunocytochemistry in fibroblasts obtained from BD patients and matched controls
Our results show that BD patient-derived fibroblasts exhibit a tendency for an increase in the levels of PGC-1α, mitochondrial transcription factor 1 (mtTFA) (p = 0.0635) and nuclear respiratory factor 1 (NRF1) that did not reach statistical significance

Summary

Introduction

Bipolar disorder (BD) is a chronic and debilitating mental disorder that affects about 45 million people worldwide [1] and is characterized by frequent changes in mood, between mania/hypomania and depression, expressed as recurrent changes in energy levels and behavior [2]. Type II is characterized by episodes of depression and hypomania [2]. This pathology usually manifests in adolescence or early adulthood, with the mean age of onset being. 20 years old, and remains throughout life [3]. To avoid recurrences of mood episodes in BD, lifetime treatment is frequently needed and is essentially pharmacological, using mood stabilizers (e.g., lithium and valproate) or atypical antipsychotics (e.g., quetiapine and aripiprazole); antidepressants are useful for acute depressive phases [2]. Delayed diagnosis/misdiagnosis is frequent, especially in early phases of BD, given that its onset is often characterized by a depressive episode, which can be classified as unipolar depression [7]. It has been suggested that cellular and molecular alterations that can modify neuronal interconnectivity play a role in the pathophysiology of BD, including mitochondrial dysfunction, endoplasmic reticulum (ER) stress, neuroinflammation, redox alterations, epigenetic changes and apoptosis [8,9,10]

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