Impact of Translocator Protein 18 kDa (TSPO) Deficiency on Mitochondrial Function and the Inflammatory State of Human C20 Microglia Cells

Bader, Stefanie; Würfel, Thea; Jahner, Tatjana; Rupprecht, Rainer; Milenkovic, Vladimir M.; Wetzel, Christian H.

doi:10.3390/cells12060954

Cited by 3 publications

(1 citation statement)

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“…All other patient astrocytes were consistently smaller than the corresponding controls; so overall, cell size remains a robust symptom/surrogate marker for patient cells. Interestingly, in a recent study where knocking down the chondrial protein TSPO resulted in mitochondrial dysfunctions, a decreased cell size was also consistently observed across different cell types [67]. These findings, in conjunction with ours, suggest a relationship between mitochondrial dysfunction and reduced cell size.…”

Section: Discussionsupporting

confidence: 86%

Mitochondrial and Cellular Function in Fibroblasts, Induced Neurons, and Astrocytes Derived from Case Study Patients: Insights into Major Depression as a Mitochondria-Associated Disease

Cardon,

Grobecker,

Kücükoktay

et al. 2024

IJMS

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The link between mitochondria and major depressive disorder (MDD) is increasingly evident, underscored both by mitochondria’s involvement in many mechanisms identified in depression and the high prevalence of MDD in individuals with mitochondrial disorders. Mitochondrial functions and energy metabolism are increasingly considered to be involved in MDD’s pathogenesis. This study focused on cellular and mitochondrial (dys)function in two atypical cases: an antidepressant non-responding MDD patient (“Non-R”) and another with an unexplained mitochondrial disorder (“Mito”). Skin biopsies from these patients and controls were used to generate various cell types, including astrocytes and neurons, and cellular and mitochondrial functions were analyzed. Similarities were observed between the Mito patient and a broader MDD cohort, including decreased respiration and mitochondrial function. Conversely, the Non-R patient exhibited increased respiratory rates, mitochondrial calcium, and resting membrane potential. In conclusion, the Non-R patient’s data offered a new perspective on MDD, suggesting a detrimental imbalance in mitochondrial and cellular processes, rather than simply reduced functions. Meanwhile, the Mito patient’s data revealed the extensive effects of mitochondrial dysfunctions on cellular functions, potentially highlighting new MDD-associated impairments. Together, these case studies enhance our comprehension of MDD.

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Section: Discussionsupporting

confidence: 86%

Mitochondrial and Cellular Function in Fibroblasts, Induced Neurons, and Astrocytes Derived from Case Study Patients: Insights into Major Depression as a Mitochondria-Associated Disease

Cardon,

Grobecker,

Kücükoktay

et al. 2024

IJMS

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Serotonin effects on human iPSC-derived neural cell functions: from mitochondria to depression

Cardon,

Grobecker,

Jenne

et al. 2024

Mol Psychiatry

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Depression’s link to serotonin dysregulation is well-known. The monoamine theory posits that depression results from impaired serotonin activity, leading to the development of antidepressants targeting serotonin levels. However, their limited efficacy suggests a more complex cause. Recent studies highlight mitochondria as key players in depression’s pathophysiology. Mounting evidence indicates that mitochondrial dysfunction significantly correlates with major depressive disorder (MDD), underscoring its pivotal role in depression. Exploring the serotonin-mitochondrial connection, our study investigated the effects of chronic serotonin treatment on induced-pluripotent stem cell-derived astrocytes and neurons from healthy controls and two case study patients. One was a patient with antidepressant non-responding MDD (“Non-R”) and another had a non-genetic mitochondrial disorder (“Mito”). The results revealed that serotonin altered the expression of genes related to mitochondrial function and dynamics in neurons and had an equalizing effect on calcium homeostasis in astrocytes, while ATP levels seemed increased. Serotonin significantly decreased cytosolic and mitochondrial calcium in neurons. Electrophysiological measurements evidenced that serotonin depolarized the resting membrane potential, increased both sodium and potassium current density and ultimately improved the overall excitability of neurons. Specifically, neurons from the Non-R patient appeared responsive to serotonin in vitro, which seemed to improve neurotransmission. While it is unclear how this translates to the systemic level and AD resistance mechanisms are not fully elucidated, our observations show that despite his treatment resistance, this patient’s cortical neurons are responsive to serotonergic signals. In the Mito patient, evidence suggested that serotonin, by increasing excitability, exacerbated an existing hyperexcitability highlighting the importance of considering mitochondrial disorders in patients with MDD, and avoiding serotonin-increasing medication. Taken together, our findings suggested that serotonin positively affects calcium homeostasis in astrocytes and increases neuronal excitability. The latter effect must be considered carefully, as it could have beneficial or detrimental implications based on individual pathologies.

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Serotonin Effects on Human iPSC-Derived Neural Cell Functions: from Mitochondria to Depression

Wetzel,

Cardon,

Grobecker

et al. 2024

Preprint

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View full text Add to dashboard Cite

Depression's link to serotonin dysregulation is well-known. The monoamine theory posits that depression results from impaired serotonin activity, leading to the development of antidepressants targeting serotonin levels. However, their limited efficacy suggests a more complex cause. Recent studies highlight mitochondria as key players in depression's pathophysiology. Mounting evidence indicates that mitochondrial dysfunction significantly correlates with major depressive disorder (MDD), underscoring its pivotal role in depression. Exploring the serotonin-mitochondrial connection, our study investigated the effects of chronic serotonin treatment on induced-pluripotent stem cell-derived astrocytes and neurons from healthy controls and two case study patients. One was a patient with antidepressant non-responding MDD ("Non-R") and another had a non-genetic mitochondrial disorder ("Mito"). The results revealed that serotonin altered the expression of genes related to mitochondrial function and dynamics in neurons and had an equalizing effect on calcium homeostasis in astrocytes, while ATP levels seemed increased. Serotonin significantly decreased cytosolic and mitochondrial calcium in neurons. Electrophysiological measurements evidenced that serotonin depolarized the resting membrane potential, increased both sodium and potassium current density and ultimately improved the overall excitability of neurons. Specifically, neurons from the Non-R patient appeared responsive to serotonin in vitro, which seemed to improve neurotransmission. While it is unclear how this translates to the systemic level and AD resistance mechanisms are not fully elucidated, our observations show that despite his treatment resistance, this patient’s cortical neurons are responsive to serotonergic signals. In the Mito patient, evidence suggested that serotonin, by increasing excitability, exacerbated an existing hyperexcitability highlighting the importance of considering mitochondrial disorders in patients with MDD, and avoiding serotonin-increasing medication. Taken together, our findings suggested that serotonin positively affects calcium homeostasis in astrocytes and increases neuronal excitability. The latter effect must be considered carefully, as it could have beneficial or detrimental implications based on individual pathologies.

show abstract

Impact of Translocator Protein 18 kDa (TSPO) Deficiency on Mitochondrial Function and the Inflammatory State of Human C20 Microglia Cells

Cited by 3 publications

References 51 publications

Mitochondrial and Cellular Function in Fibroblasts, Induced Neurons, and Astrocytes Derived from Case Study Patients: Insights into Major Depression as a Mitochondria-Associated Disease

Mitochondrial and Cellular Function in Fibroblasts, Induced Neurons, and Astrocytes Derived from Case Study Patients: Insights into Major Depression as a Mitochondria-Associated Disease

Serotonin effects on human iPSC-derived neural cell functions: from mitochondria to depression

Serotonin Effects on Human iPSC-Derived Neural Cell Functions: from Mitochondria to Depression

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