钼和镉共同暴露通过亚细胞钙重分布诱导鸭肾小管上皮细胞钙调蛋白激酶 β/AMPK/mTOR 通路介导的自噬。
Molybdenum and cadmium co-exposure induces CaMKKβ/AMPK/mTOR pathway mediated-autophagy by subcellular calcium redistribution in duck renal tubular epithelial cells.
机构信息
Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China.
Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China..
出版信息
J Inorg Biochem. 2022 Nov;236:111974. doi: 10.1016/j.jinorgbio.2022.111974. Epub 2022 Aug 19.
Excessive molybdenum (Mo) and cadmium (Cd) are toxic environmental pollutants. Our previous research confirmed excessive Mo and Cd co-induced calcium homeostasis disorder and autophagy in duck kidneys, but how calcium ion (Ca) regulates autophagy is unclear. The results revealed that the Mo- and/or Cd-induced cytosolic Ca concentration ([Ca]) increase mainly came from intracellular calcium stores. Mo and/or Cd caused mitochondrial Ca content ([Ca]) and [Ca] increase with endoplasmic reticulum (ER) Ca content ([Ca]) decrease and upregulated calcium homeostasis-related factor expression levels, but 2-Aminoethoxydiphenyl borate (2-APB) reversed subcellular Ca redistribution. Increased Phospholipase C (PLC) and inositol 1,4,5-trisphosphate (IP) activities and inositol 1,4,5-trisphosphate receptor (IPR) expression level were observed in Mo- and/or Cd-treated cells, which was reversed by the PLC inhibitor U-73122. 2-APB and 1,2-Bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) addition mitigated [Ca] and autophagy (variations in microtubule-associated protein light chain 3 (LC3), LC3B-II/LC3B-I, autophagy related 5 (ATG5), sequestosome-1(P62), programmed cell death-1 (Beclin-1) and Dynein expression levels, LC3 puncta, autophagosomes and acid vesicle organelles) under Mo and/or Cd treatment, respectively, while thapsigargin (TG) had the opposite impacts. Additionally, the calmodulin-dependent protein kinase kinase β (CaMKKβ) inhibitor STO-609 reversed the increased CaMKKβ, adenosine 5'-monophosphate-activated protein kinase (AMPK), Beclin-1, and LC3B-II/LC3B-I protein expression levels and reduced mammalian target of rapamycin (mTOR) and P62 protein expression levels in Mo- and/or Cd-exposed cells. Collectively, the results confirmed that [Ca] overload resulted from PLC/IP/IPR pathway-mediated ER Ca release, and then activated autophagy by the CaMKKβ/AMPK/mTOR pathway in Mo- and/or Cd-treated duck renal tubular epithelial cells.
过量的钼（Mo）和镉（Cd）是有毒的环境污染物。我们之前的研究证实，过量的 Mo 和 Cd 共同诱导鸭肾脏中的钙稳态紊乱和自噬，但钙离子（Ca）如何调节自噬尚不清楚。结果表明，Mo 和/或 Cd 诱导的细胞质 Ca 浓度（[Ca]）增加主要来自细胞内钙库。Mo 和/或 Cd 导致线粒体 Ca 含量（[Ca]）和 [Ca]增加，内质网（ER）Ca 含量（[Ca]）减少，钙稳态相关因子表达水平上调，但 2-APB 逆转了亚细胞 Ca 再分布。Mo 和/或 Cd 处理的细胞中观察到磷酸脂酶 C（PLC）和肌醇 1,4,5-三磷酸（IP）活性以及肌醇 1,4,5-三磷酸受体（IPR）表达水平增加，这些变化可被 PLC 抑制剂 U-73122 逆转。2-APB 和 1,2-双（2-氨基苯氧基）乙烷-N,N,N',N'-四乙酸乙酰氧基甲酯（BAPTA-AM）的添加减轻了 [Ca]和自噬（微管相关蛋白轻链 3（LC3）、LC3B-II/LC3B-I、自噬相关蛋白 5（ATG5）、自噬相关蛋白 12（P62）、程序性细胞死亡蛋白 1（Beclin-1）和动力蛋白表达水平、LC3 斑点、自噬体和酸性囊泡细胞器）在 Mo 和/或 Cd 处理下的变化，而 thapsigargin（TG）则产生相反的影响。此外，钙调蛋白依赖性蛋白激酶激酶β（CaMKKβ）抑制剂 STO-609 逆转了 Mo 和/或 Cd 暴露细胞中 CaMKKβ、腺苷 5'-单磷酸激活蛋白激酶（AMPK）、Beclin-1 和 LC3B-II/LC3B-I 蛋白表达水平的增加以及哺乳动物雷帕霉素靶蛋白（mTOR）和 P62 蛋白表达水平的降低。总之，结果证实，[Ca]超载是由 PLC/IP/IPR 途径介导的 ER Ca 释放引起的，然后通过 CaMKKβ/AMPK/mTOR 途径激活 Mo 和/或 Cd 处理的鸭肾小管上皮细胞中的自噬。
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