Toll‐like receptor 9 protects non‐immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA 2

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.

Resistance of Dynamin-related Protein 1 Oligomers to Disassembly Impairs Mitophagy, Resulting in Myocardial Inflammation and Heart Failure

“…Activation of cardiac inflammatory nodes, specifically TLR9, influences mitochondrial cal- cium by inhibition of SERCA2, reducing mitochondrial calcium uptake and ATP synthesis (40). This has been interpreted as a stress protection response in cardiomyocytes but might also be detrimental when activated long-term, leading to functional ATP deficiency.…”

Extracellular calcium elicits feedforward regulation of the Toll-like receptor-triggered innate immune response

“…Ca 21 signals are crucial for the control of a broad range of cellular functions. 20,21 Upon TLR stimulation, intracellular calcium levels are increased, [34][35][36][37][38][39] either from internal stores in the ER lumen or from influx from the extracellular space. Previous studies have suggested that increased intracellular calcium plays important roles in mediating the TLR-triggered immune response.…”

“…Previous studies have suggested that increased intracellular calcium plays important roles in mediating the TLR-triggered immune response. [35][36][37][38][39][40][41][42][43][44][45][46][47] In most studies, attention has been paid to intracellular calcium mobilization. However, TLRs may trigger calcium release from the ER and then STIM-ORAImediated calcium entry.…”

Higd1a is a positive regulator of cytochrome c oxidase

“…FRET-based measurement of mitochondrial ATP concentration in cardiomyocytes was measured as previously described (8,33). Briefly, FRET signal was measured in cardiomyocytes infected with adenovirus encoding mit-AT1.03 with an Olympus IX-81 inverted fluorescence microscope (Olympus) using a PL APO 60×, 1.35 N.A., oil immersion objective lens (Olympus).…”