N -(3-Oxo-acyl)-homoserine lactone induces apoptosis primarily through a mitochondrial pathway in fibroblasts

Abstract

N-(3-Oxododecanoyl)-L-homoserine lactone (C12) is produced by Pseudomonas aeruginosa to function as a quorum-sensing molecule for bacteria-bacteria communication. C12 is also known to influence many aspects of human host cell physiology, including induction of cell death.However, the signalling pathway(s) leading to C12-triggered cell death is (are) still not completely known. To clarify cell death signalling induced by C12, we examined mouse embryonic fibroblasts deficient in "initiator" caspases or "effector" caspases. Our data indicate that C12 selectively induces the mitochondria-dependent intrinsic apoptotic pathway by quickly triggering mitochondrial outer membrane permeabilisation. Importantly, the activities of C12 to permeabilise mitochondria are independent of activation of both "initiator" and "effector" caspases. Furthermore, C12 directly induces mitochondrial outer membrane permeabilisation in vitro. Overall, our study suggests a mitochondrial apoptotic signalling pathway triggered by C12, in which C12 or its metabolite(s) acts on mitochondria to permeabilise mitochondria, leading to activation of apoptosis.

Overexpression of ATP citrate lyase in renal cell carcinoma tissues and its effect on the human renal carcinoma cells in�vitro

“…Additionally, the possible mechanism for anti-apoptosis effect of ACLY in RCC may be related with promotion of lipogenesis in mitochondria, because inhibition of ACLY would impair lipogenesis, involving activation of AMPK and blocking of its downstream protein ACC1 ( 25 ), further mitochondrial function would be impaired ( 26 ). Moreover, intrinsic apoptotic pathway is the mitochondria-dependent in some extent ( 27 ). Therefore, a deep understanding of the role of high ACLY expression may provide opportunities to find novel and more effective therapeutic approaches.…”

“…Although the precise mechanisms for the anti-apoptosis effect of ACLY remain unclear, ACLY inhibition impairs lipogenesis, which involves AMPK activation and blockage of its downstream protein ACC1 ( 32 ), and impairs mitochondrial function ( 26 ). Moreover, the intrinsic apoptotic pathway is mitochondria-dependent to some extent ( 27 ). We, therefore, suggest that the anti-apoptosis effect of ACLY in RCC may be related to the advancement of lipogenesis in mitochondria.…”

The intestinal quorum sensing 3-oxo-C12:2 Acyl homoserine lactone limits cytokine-induced tight junction disruption

“…C12 stands for 3-oxo-C12; C12:2 stands for 3-oxo-C12:2. and 3-oxo-C12 (Figure 7b), in accordance with studies showing that this AHL induces apoptosis in several cell types. 52,54,55 Regarding 3-oxo-C12:2, this AHL did not prevent cytokine-induced hyperpermeability, despite clear protective effects on TJ integrity and stability. Given that this AHL decreased neither cell toxicity nor apoptosis induced by cytokines (not shown), we assume that cell death hid beneficial effects of TJ-protecting 3-oxo-C12:2 AHL on epithelial permeability (Figure 7c).…”

Pseudomonas aeruginosa N-3-Oxo-Dodecanoyl-Homoserine Lactone Impacts Mitochondrial Networks Morphology, Energetics, and Proteome in Host Cells

“…Additionally, 3O-C 12 -HSL has been demonstrated to influence mitochondrial physiology in fibroblasts by releasing cytochrome c via activating caspases 3/7 and 8 without the involvement of Bak/Bax regulators of apoptosis, i.e., having a pro-apoptotic effect (Schwarzer et al, 2014). 3O-C 12 -HSL may trigger apoptosis and cytotoxicity in many type of cells (Tateda et al, 2003;Schwarzer et al, 2012;Zhao et al, 2016;Neely et al, 2018) and this was recently reviewed (Guo et al, 2020). Still, fibroblasts and polarized human epithelial cells used in this study (Supplementary Figure S1) and earlier (Karlsson et al, 2012b;Losa et al, 2015) and human primary neutrophils and macrophages (Karlsson et al, 2012a;Holm et al, 2016), did not display any apoptotic changes or cell death in response to 3O-C 12 -HSL in the used conditions.…”