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

ABSTRACT: Hypocapnia, a reduction in partial pressure of carbon dioxide (CO₂), commonly occurs in clinical contexts such as mechanical ventilation, panic disorder, and brain injury. 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. Concurrently, suppressed AMPK activity and sustained mTOR signaling revealed a unique metabolic state, uncoupling energy stress from canonical autophagy signaling. As such, mTORC1/2 inhibition was capable of rescuing the impaired autophagy. Notably, increased pH was not sufficient to drive this program. These findings identify hypocapnia as a previously unrecognized modulator of autophagy that disrupts autophagosome-lysosome fusion and terminal degradation, positioning CO₂ tension as a critical regulator of cellular stress responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE329632 | GEO | 2026/06/19

REPOSITORIES: GEO

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