- Main
Acid Suspends the Circadian Clock in Hypoxia through Inhibition of mTOR
- Walton, Zandra E;
- Patel, Chirag H;
- Brooks, Rebekah C;
- Yu, Yongjun;
- Ibrahim-Hashim, Arig;
- Riddle, Malini;
- Porcu, Alessandra;
- Jiang, Tianying;
- Ecker, Brett L;
- Tameire, Feven;
- Koumenis, Constantinos;
- Weeraratna, Ashani T;
- Welsh, David K;
- Gillies, Robert;
- Alwine, James C;
- Zhang, Lin;
- Powell, Jonathan D;
- Dang, Chi V
- et al.
Published Web Location
https://doi.org/10.1016/j.cell.2018.05.009Abstract
Recent reports indicate that hypoxia influences the circadian clock through the transcriptional activities of hypoxia-inducible factors (HIFs) at clock genes. Unexpectedly, we uncover a profound disruption of the circadian clock and diurnal transcriptome when hypoxic cells are permitted to acidify to recapitulate the tumor microenvironment. Buffering against acidification or inhibiting lactic acid production fully rescues circadian oscillation. Acidification of several human and murine cell lines, as well as primary murine T cells, suppresses mechanistic target of rapamycin complex 1 (mTORC1) signaling, a key regulator of translation in response to metabolic status. We find that acid drives peripheral redistribution of normally perinuclear lysosomes away from perinuclear RHEB, thereby inhibiting the activity of lysosome-bound mTOR. Restoring mTORC1 signaling and the translation it governs rescues clock oscillation. Our findings thus reveal a model in which acid produced during the cellular metabolic response to hypoxia suppresses the circadian clock through diminished translation of clock constituents.
Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.
Main Content
Enter the password to open this PDF file:
-
-
-
-
-
-
-
-
-
-
-
-
-
-