Tuberous Sclerosis Complex (
TSC) is a multisystem
genetic disorder characterized by the development of benign
tumors in various organs, including the brain, and is often accompanied by
epilepsy, neurodevelopmental comorbidities including
intellectual disability and
autism. A key hallmark of
TSC is the hyperactivation of the mechanistic target of
rapamycin (mTOR) signaling pathway, which induces alterations in cortical development and metabolic processes in astrocytes, among other cellular functions. These changes could modulate seizure susceptibility, contributing to the progression of
epilepsy and its associated comorbidities.
Epilepsy is characterized by dysregulation of
calcium (Ca2+) channels and intracellular Ca2+ dynamics. These factors contribute to hyperexcitability, disrupted synaptogenesis, and altered synchronization of neuronal networks, all of which contribute to seizure activity. This study investigates the intricate interplay between altered Ca2+ dynamics, mTOR pathway dysregulation, and cellular metabolism in astrocytes. The transcriptional profile of
TSC patients revealed significant alterations in pathways associated with cellular respiration, ER and mitochondria, and Ca2+ regulation.
TSC astrocytes exhibited lack of responsiveness to various stimuli, compromised oxygen consumption rate and reserve respiratory capacity underscoring their reduced capacity to react to environmental changes or cellular stress. Furthermore, our study revealed significant reduction of store operated
calcium entry (SOCE) along with strong decrease of basal mitochondrial Ca2+ concentration and Ca2+ influx in
TSC astrocytes. In addition, we observed alteration in mitochondrial membrane potential, characterized by increased depolarization in
TSC astrocytes. Lastly, we provide initial evidence of structural abnormalities in mitochondria within
TSC patient-derived astrocytes, suggesting a potential link between disrupted Ca2+ signaling and
mitochondrial dysfunction. Our findings underscore the complexity of the relationship between Ca2+ signaling, mitochondria dynamics, apoptosis, and mTOR hyperactivation. Further exploration is required to shed light on the pathophysiology of
TSC and on
TSC associated neuropsychiatric disorders offering further potential avenues for therapeutic development.