Romagnolo 2024 Acta Neuropathol

Romagnolo A, Dematteis G, Scheper M, Luinenburg MJ, Mühlebner A, Van Hecke W, Manfredi M, De Giorgis V, Reano S, Filigheddu N, Bortolotto V, Tapella L, Anink JJ, François L, Dedeurwaerdere S, Mills JD, Genazzani AA, Lim D, Aronica E (2024) Astroglial calcium signaling and homeostasis in tuberous sclerosis complex. Acta Neuropathol 147:48. https://doi.org/10.1007/s00401-024-02711-3

» PMID: 38418708 Open Access

Romagnolo Alessia, Dematteis Giulia, Scheper Mirte, Luinenburg Mark J, Muehlebner Angelika, Van Hecke Wim, Manfredi Marcello, De Giorgis Veronica, Reano Simone, Filigheddu Nicoletta, Bortolotto Valeria, Tapella Laura, Anink Jasper J, Francois Liesbeth, Dedeurwaerdere Stefanie, Mills James D, Genazzani Armando A, Lim Dmitry, Aronica Eleonora (2024) Acta Neuropathol

Abstract: 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. • Keywords: Astrocytes, Calcium signaling, Epilepsy, Mitochondria, Tuberous sclerosis complex, mTOR • Bioblast editor: Plangger M • O2k-Network Lab: IT Novara Filigheddu N

Labels: MiParea: Respiration 

Organism: Human  Tissue;cell: Nervous system  Preparation: Intact cells 

Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k 

2024-03