巡逻蛋白通过溶酶体-线粒体轴和HepG2细胞线粒体受损诱导自噬依赖性细胞凋亡。,Journal of Agricultural and Food Chemistry

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巡逻蛋白通过溶酶体-线粒体轴和HepG2细胞线粒体受损诱导自噬依赖性细胞凋亡。
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2018-11-04 00:00:00 , DOI: 10.1021/acs.jafc.8b03922
Ming Sun ₁ , Shaopeng Wang ₂ , Liping Jiang ₃ , Yueran Bai ₁ , Xiance Sun ₃ , Jing Li ₄ , Bo Wang ₄ , Xiaofeng Yao ₃ , Xiaofang Liu ₁ , Qiujuan Li ₃ , Chengyan Geng ₃ , Cong Zhang ₁ , Guang Yang ₁

Affiliation

棒曲霉素（PAT）是由真菌产生的化合物，包括曲霉菌，青霉菌和Byssochlamys菌。PAT已与某些微生物和动物物种的阴性结果相关联，但人们对它如何引起肝毒性的了解却很少。在这项研究中，我们确定，通过使用PAT处理HepG2细胞，可以诱导这些细胞快速自噬，然后在溶酶体膜通透性（LMP）和组织蛋白酶B释放的处理后12小时内。如果在PAT治疗之前用3-甲基腺嘌呤（3MA）（自噬抑制剂）处理细胞，我们就能阻止这些结果。此外，PAT诱导的线粒体膜电位（ΔΨm）崩溃取决于组织蛋白酶B和自噬。3MA进一步减少了对PAT的凋亡诱导作用，提示自噬是这种凋亡诱导的驱动机制。使用CA-074 Me抑制组织蛋白酶B可进一步减少PAT诱导的ΔΨm，线粒体细胞色素的塌陷c释放，并凋亡。我们还发现，在24小时内使用PAT延长HepG2细胞的治疗会导致线粒体受损，从而导致线粒体在形态上在细胞内积累，而PINK1无法与LC3共定位。这些数据共同表明，PAT治疗可以通过依赖自溶的方式（通过溶酶体-线粒体轴进行）来促进HepG2细胞凋亡的诱导。因此，该研究为PAT驱动肝毒性的机制提供了新见解。

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Patulin Induces Autophagy-Dependent Apoptosis through Lysosomal-Mitochondrial Axis and Impaired Mitophagy in HepG2 Cells

Patulin (PAT) is a compound produced by fungi including those of the Aspergillus, Penicillium, and Byssochlamys species. PAT has been linked with negative outcomes in certain microorganisms and animal species, but how it causes hepatotoxicity is poorly understood. In this study, we determined that, by treating HepG2 cells using PAT, these cells could be induced to rapidly undergo autophagy, and this was followed within 12 h of treatment by lysosomal membrane permeabilization (LMP) and cathepsin B release. We were able to block these outcomes if cells were treated with 3-methyladenine (3MA), an inhibitor of autophagy, prior to PAT treatment. Moreover, PAT-induced collapse of mitochondrial membrane potential (ΔΨm) depended both on cathepsin B and autophagy. 3MA was further able to reduce the induction of apoptosis in response to PAT, suggesting that autophagy is a driving mechanism for this apoptotic induction. Inhibiting cathepsin B using CA-074 Me further reduced PAT-induced collapses of ΔΨm, mitochondiral cytochrome c release, and apoptosis. We also found that extended treatment of HepG2 cells using PAT over a period of 24 h led to the impairment of mitophagy such that morphologically swollen mitochondria accumulated within cells, and PINK1 failed to colocalize with LC3. Together these data reveal that PAT treatment can promote the induction of apoptosis in HepG2 cells in a manner dependent upon autophagy that progresses via the lysosomal-mitochondrial axis. This study thereby affords new insights into the mechanisms by which PAT drives hepatotoxicity.

更新日期：2018-11-04

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