Toll-like receptor 9 protects non-immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2

Yasunori Shintani, Hannes C A Drexler, Hidetaka Kioka, Cesare M N Terracciano, Steven R Coppen, Hiromi Imamura, Masaharu Akao, Junichi Nakai, Ann P Wheeler, Shuichiro Higo, Hiroyuki Nakayama, Seiji Takashima, Kenta Yashiro, Ken Suzuki

Research output: Contribution to journalArticlepeer-review

Abstract

Toll-like receptor 9 (TLR9) has a key role in the recognition of pathogen DNA in the context of infection and cellular DNA that is released from damaged cells. Pro-inflammatory TLR9 signalling pathways in immune cells have been well investigated, but we have recently discovered an alternative pathway in which TLR9 temporarily reduces energy substrates to induce cellular protection from stress in cardiomyocytes and neurons. However, the mechanism by which TLR9 stimulation reduces energy substrates remained unknown. Here, we identify the calcium-transporting ATPase, SERCA2 (also known as Atp2a2), as a key molecule for the alternative TLR9 signalling pathway. TLR9 stimulation reduces SERCA2 activity, modulating Ca(2+) handling between the SR/ER and mitochondria, which leads to a decrease in mitochondrial ATP levels and the activation of cellular protective machinery. These findings reveal how distinct innate responses can be elicited in immune and non-immune cells--including cardiomyocytes--using the same ligand-receptor system.

Original languageEnglish
Pages (from-to)438-45
Number of pages8
JournalEMBO Reports
Volume15
Issue number4
DOIs
Publication statusPublished - Apr 2014

Keywords

  • Adenosine Triphosphate
  • Animals
  • Calcium
  • Calcium Signaling
  • Cells, Cultured
  • Endoplasmic Reticulum
  • Fibroblasts
  • Mice
  • Mitochondria
  • Myocytes, Cardiac
  • Protein Binding
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Stress, Physiological
  • Toll-Like Receptor 9

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