Neurotherapeutic implications of sense and respond strategies generated by astrocytes and astrocytic tumours to combat pH mechanical stress

Abstract Aims Astrocytes adapt to acute acid stress. Intriguingly, cancer cells with astrocytic differentiation thrive even better in an acidic microenvironment. How changes in extracellular pH (pHe) are sensed and measured by the cell surface assemblies that first intercept the acid stress, and how this information is relayed downstream for an appropriate survival response remains largely uncharacterized. Methods In vitro cell‐based studies were combined with an in vivo animal model to delineate the machinery involved in pH microenvironment sensing and generation of mechanoadaptive responses in normal and neoplastic astrocytes. The data was further validated on patient samples from acidosis driven ischaemia and astrocytic tumour tissues. Results We demonstrate that low pHe is perceived and interpreted by cells as mechanical stress. GM3 acts as a lipid‐based pH sensor, and in low pHe, its highly protonated state generates plasma membrane deformation stress which activates the IRE1‐sXBP1‐SREBP2‐ACSS2 response axis for cholesterol biosynthesis and surface trafficking. Enhanced surface cholesterol provides mechanical tenacity and prevents acid‐mediated membrane hydrolysis, which would otherwise result in cell leakage and death. Conclusions In summary, activating these lipids or the associated downstream machinery in acidosis‐related neurodegeneration may prevent disease progression, while specifically suppressing this key mechanical ‘sense‐respond’ axis should effectively target astrocytic tumour growth.