Molybdenum and/or cadmium induce NLRP3 inflammasome production by causing mitochondria-associated endoplasmic reticulum membrane dysfunction in sheep hepatocytes

Accumulation of the heavy metals molybdenum (Mo) and cadmium (Cd) in the liver can induce organelle damage and inflammation, resulting in hepatotoxicity. The effect of Mo and/or Cd on sheep hepatocytes was investigated by determining the relationship between the mitochondria-associated endoplasmic reticulum membrane (MAM) and NLRP3 inflammasome. Sheep hepatocytes were divided into four groups: the control group, Mo group (600 & mu;M Mo), Cd group (4 & mu;M Cd) and Mo + Cd group (600 & mu;M Mo+4 & mu;M Cd). The results showed that Mo and/or Cd exposure increased the levels of lactate dehydrogenase (LDH) and nitric oxide (NO) in the cell culture supernatant, elevated the levels of intracellular Ca2+ and mitochondrial Ca2+, downregulated the expression of MAM-related factors (IP3R, GRP75, VDAC1, PERK, ERO1-a, Mfn1, Mfn2, ERP44), shortened the length of the MAM and reduced the formation of the MAM structure, eventually causing MAM dysfunction. Moreover, the expression levels of NLRP3 inflammasome-related factors (NLRP3, Caspase1, IL-1(i, IL-6, TNF-a) were also dramatically increased after Mo and Cd exposure, triggering NLRP3 inflammasome production. However, an IP3R inhibitor, 2-APB treatment significantly alleviated these changes. Overall, the data indicate that Mo and Cd coexposure leads to structural disruption and dysfunction of MAM, disrupts cellular Ca2+ homeostasis, and increases NLRP3 inflammasome production in sheep hepatocytes. However, the inhibition of IP3R alleviates NLRP3 inflammasome production induced by Mo and Cd.

Automated summary

Accumulation of heavy metals molybdenum and cadmium in the liver can lead to damage and inflammation in the cells, causing hepatotoxicity. The study investigated the effects of molybdenum and/or cadmium on sheep hepatocytes by examining the relationship between mitochondria-associated endoplasmic reticulum membrane (MAM) and NLRP3 inflammasome. The results showed that exposure to molybdenum and/or cadmium increased lactate dehydrogenase and nitric oxide levels, disrupted cellular calcium homeostasis, and induced inflammation. Inhibiting IP3R alleviated NLRP3 inflammasome production induced by molybdenum and cadmium.