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Oxalate Alters Cellular Bioenergetics, Redox Homeostasis, Antibacterial Response, and Immune Response in Macrophages

ABSTRACT: Individuals with calcium oxalate (CaOx) kidney stones can have secondarily infected calculi which may play a role in the development of recurrent urinary tract infection (UTI). Uropathogenic Escherichia coli (UPEC) is the most common causative pathogen of UTIs. Macrophages play a critical role in host immune defense against bacterial infections. Our previous study demonstrated that oxalate, an important component of the most common type of kidney stone, impairs monocyte cellular bioenergetics and redox homeostasis. The objective of this study was to investigate whether oxalate compromises macrophage metabolism, redox status, anti-bacterial response, and immune response. Monocytes (THP-1, a human monocytic cell line) were exposed to sodium oxalate (soluble oxalate; 50 µM) for 48 hours prior to being differentiated into macrophages. Macrophages were subsequently exposed to calcium oxalate crystals (50 µM) for 48 hours followed by UPEC (MOI 1:2 or 1:5) for 2 hours. Peritoneal macrophages and bone marrow-derived macrophages (BMDM) from C57BL/6 mice were also exposed to oxalate. THP-1 macrophages treated with oxalate had decreased cellular bioenergetics, mitochondrial complex I and IV activity, and ATP levels compared to control cells. In addition, these cells had a significant increase in mitochondrial and total reactive oxygen species levels, mitochondrial gene expression, and pro-inflammatory cytokine (i.e. Interleukin-1β, IL-1β and Interleukin-6, IL-6) mRNA levels and secretion. In contrast, oxalate significantly decreased the mRNA levels and secretion of the anti-inflammatory cytokine, Interleukin-10 (IL-10). Further, oxalate increased the bacterial burden of primary macrophages. Our findings demonstrate that oxalate compromises macrophage metabolism, redox homeostasis, and cytokine signaling leading to a reduction in anti-bacterial response and increased infection. These data highlight a novel role of oxalate on macrophage function.

SUBMITTER: Kumar P

PROVIDER: S-EPMC8566947 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Artesunate (ART) is a prominent anti-malarial with significant anti-cancer properties. Our previous studies showed that ART enhances lysosomal function and ferritin degradation, which was necessary for its anti-cancer properties. ART targeting to mitochondria also significantly improved its efficacy, but the effect of ART on mitophagy, an important cellular pathway that facilitates the removal of damaged mitochondria, remains unknown. Here, we first observed that ART mainly localizes in the mitochondria and its probe labeling revealed that it binds to a large number of mitochondrial proteins and causes mitochondrial fission. Second, we found that ART treatment leads to autophagy induction and the decrease of mitochondrial proteins. When autophagy is inhibited, the decrease of mitochondrial proteins could be reversed, indicating that the degradation of mitochondrial proteins is through mitophagy. Third, our results showed that ART treatment stabilizes the full-length form of PTEN induced putative kinase 1 (PINK1) on the mitochondria and activates the PINK1-dependent pathway. This in turn leads to the recruitment of Parkin, sequestosome 1 (SQSTM1), ubiquitin and microtubule-associated proteins 1A/1B light chain 3 (LC3) to the mitochondria and culminates in mitophagy. When PINK1 is knocked down, ART-induced mitophagy is markedly suppressed. Finally, we investigated the effect of mitophagy by ART on mitochondrial functions and found that knockdown of PINK1 alters the cellular redox status in ART-treated cells, which is accompanied with a significant decrease in glutathione (GSH) and increase in mitochondrial reactive oxidative species (mROS) and cellular lactate levels. Additionally, knockdown of PINK1 leads to a significant increase of mitochondrial depolarization and more cell apoptosis by ART, suggesting that mitophagy protects from ART-induced cell death. Taken together, our findings reveal the molecular mechanism that ART induces cytoprotective mitophagy through the PINK1-dependent pathway, suggesting that mitophagy inhibition could enhance the anti-cancer activity of ART.

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Oxalate Alters Cellular Bioenergetics, Redox Homeostasis, Antibacterial Response, and Immune Response in Macrophages

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