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

Overview

1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
2. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA

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, yet 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 but, paradoxically, reduced autophagosome-lysosome fusion and lysosomal proteolytic activity. Mechanistically, hypocapnia promoted TFE3 dephosphorylation and nuclear translocation, driving transcriptional activation of lysosomal genes. Concurrently, suppressed AMPK activity and sustained mTOR signaling revealed a unique metabolic state that uncouples energy stress from canonical autophagy control. As such, inhibition of both mTORC1 and mTORC2 was sufficient to restore autophagic flux. 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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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• geo:GSE329632 — at NCBI GEO; found in the end of the paper

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 3 authors, 6 keywords, 10 MeSH terms, 2 funders, 32 references.

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This paper

Ashraf, N., Sun, Z., & Van Nostrand, J. L. (2026). Autophagic flux blockade under hypocapnia reveals CO2-sensitive regulation of autophagy-lysosome homeostasis. Biology open, 15(6), bio062414. https://doi.org/10.1242/bio.062414

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