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 and Ken Suzuki ()
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Yasunori Shintani: Queen Mary University of London
Hannes CA Drexler: Max Planck Institute for Molecular Biomedicine
Hidetaka Kioka: Osaka University Graduate School of Medicine
Cesare MN Terracciano: Imperial College London, National Heart & Lung Institute, Hammersmith Campus
Steven R Coppen: Queen Mary University of London
Hiromi Imamura: Kyoto University Science Frontier Laboratory building Room 305
Masaharu Akao: National Hospital Organization Kyoto Medical Center
Junichi Nakai: Saitama University Brain Science Institute
Ann P Wheeler: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Shuichiro Higo: Osaka University Graduate School of Medicine
Hiroyuki Nakayama: Osaka University Graduate School of Pharmaceutical Sciences
Seiji Takashima: Osaka University Graduate School of Medicine
Kenta Yashiro: Queen Mary University of London
Ken Suzuki: Queen Mary University of London

Nature, 2014, vol. 15, issue 4, 438-445

Abstract: 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.

Keywords: danger signal; DNA; SERCA2; TLR9 (search for similar items in EconPapers)
Date: 2014
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DOI: 10.1002/embr.201337945

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