Autophagic flux blockade under hypocapnia reveals CO₂-sensitive regulation of autophagy-lysosome homeostasis

However, its impact on cellular homeostasis remains poorly understood. Given the central role of autophagy in stress adaptation, we investigated how low CO₂ influences autophagic flux and lysosomal function.

We found that hypocapnia induces autophagosome accumulation while impairing cargo degradation, indicating a blockade in autophagic flux. This response was accompanied by increased lysosome biogenesis yet, paradoxically, reduced lysosomal fusion and proteolytic activity. Mechanistically, hypocapnia promoted TFE3 dephosphorylation and nuclear translocation, driving transcriptional activation of the lysosomal program.