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

Yasunori Shintani, Hannes Ca Drexler, Hidetaka Kioka, Cesare Mn 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

43 Citations (Scopus)

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 Ca2+ 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. Synopsis TLR9 signalling has recently been shown to protect cardiomyocytes and neurons from stress by modulating energy metabolism. This study shows that it does so by inhibiting SERCA2 activity and thus the Ca2+ transfer between SR/ER and mitochondria. SERCA2 is a key adaptor for the alternative TLR9 signalling pathway. SERCA2 inhibition by TLR9 modulates Ca2+ handling between the SR/ER and mitochondria. A decrease in mitochondrial Ca2+ and subsequent ATP synthesis activates cellular protective machinery. TLR9 signalling has recently been shown to protect cardiomyocytes and neurons from stress by modulating energy metabolism. This study shows that it does so by inhibiting SERCA2 activity and thus the Ca2+ transfer between SR/ER and mitochondria.

Original languageEnglish
Pages (from-to)438-445
Number of pages8
JournalEMBO Reports
Volume15
Issue number4
DOIs
Publication statusPublished - 2014 Apr
Externally publishedYes

Keywords

  • DNA
  • SERCA2
  • TLR9
  • danger signal

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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