Mitochondria directly sense osmotic stress to trigger rapid metabolic remodeling via regulation of pyruvate dehydrogenase phosphorylation

Takeshi Ikizawa, Kazutaka Ikeda, Makoto Arita, Shojiro Kitajima, Tomoyoshi Soga, Hidenori Ichijo, Isao Naguro

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

A high-salt diet significantly impacts various diseases, ilncluding cancer and immune diseases. Recent studies suggest that the high-salt/hyperosmotic environment in the body may alter the chronic properties of cancer and immune cells in the disease context. However, little is known about the acute metabolic changes in hyperosmotic stress. Here, we found that hyperosmotic stress for a few minutes induces Warburg-like metabolic remodeling in HeLa and Raw264.7 cells and suppresses fatty acid oxidation. Regarding Warburg-like remodeling, we determined that the pyruvate dehydrogenase phosphorylation status was altered bidirectionally (high in hyperosmolarity and low in hypoosmolarity) to osmotic stress in isolated mitochondria, suggesting that mitochondria themselves have an acute osmosensing mechanism. Additionally, we demonstrate that Warburg-like remodeling is required for HeLa cells to maintain ATP levels and survive under hyperosmotic conditions. Collectively, our findings suggest that cells exhibit acute metabolic remodeling under osmotic stress via the regulation of pyruvate dehydrogenase phosphorylation by direct osmosensing within mitochondria.

Original languageEnglish
Article number102837
JournalJournal of Biological Chemistry
Volume299
Issue number2
DOIs
Publication statusPublished - 2023 Feb

Keywords

  • acyl-carnitine
  • metabolic remodeling
  • mitochondria
  • osmotic stress
  • pyruvate dehydrogenase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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