Resting Ca²⁺ fluxes protect cells from fast mitochondrial fragmentation, cell stress responses, and immediate transcriptional reprogramming

Area of Science:

• Cell Biology
• Molecular Biology
• Neuroscience

Background:

• Homeostatic calcium ion (Ca²⁺) fluxes occur continuously between cellular compartments.
• These resting fluxes are essential for maintaining cellular homeostasis, even in unstimulated cells.

Purpose of the Study:

• To investigate the signaling function of resting Ca²⁺ fluxes in murine astrocytes.
• To understand the role of endoplasmic reticulum (ER) Ca²⁺ levels in cellular stress responses.

Main Methods:

• Murine astrocytes were used as a model system.
• Sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibition and Ca²⁺-free medium were employed to induce ER Ca²⁺ depletion.
• Store-operated Ca²⁺ entry (SOCE) and STIM proteins were manipulated to assess their impact.
• Transcriptome analysis was performed to evaluate gene expression changes.
• PERK phosphorylation was measured as an indicator of ER stress.

Main Results:

• ER Ca²⁺ depletion led to prolonged Ca²⁺ influx, mitochondrial fragmentation, and significant changes in gene expression within an hour.
• Mitochondrial fragmentation was preventable by removing extracellular Ca²⁺ or inhibiting SOCE.
• PERK (EIF2AK3) phosphorylation, a marker of ER stress, was rapidly induced by ER Ca²⁺ depletion.
• Resting Ca²⁺ fluxes were found to prevent immediate-early cell stress and transcriptional reprogramming.

Conclusions:

• Resting Ca²⁺ fluxes play a vital signaling role in preventing cellular stress.
• Maintaining ER Ca²⁺ levels through homeostatic fluxes is critical for mitochondrial integrity and preventing transcriptional changes.
• These findings highlight the importance of continuous calcium signaling in cellular homeostasis.