Abstract：
Perfluorooctane sulfonate (PFOS), an officially listed persistent organic pollutant, is a widely distributed perfluoroalkyl substance. Epidemiological studies have shown that PFOS is intimately linked to the occurrence of insulin resistance (IR). However, the detailed mechanism remains obscure. In previous studies, we found that mitochondrial calcium overload was concerned with hepatic IR induced by PFOS. In this study, we found that PFOS exposure noticeably raised lysosomal calcium in L-02 hepatocytes from 0.5 h. In the PFOS-cultured L-02 cells, inhibiting autophagy alleviated lysosomal calcium overload. Inhibition of mitochondrial calcium uptake aggravated the accumulation of lysosomal calcium, while inhibition of lysosomal calcium outflowing reversed PFOS-induced mitochondrial calcium overload and IR. Transient receptor potential mucolipin 1 (TRPML1), the calcium output channel of lysosomes, interacted with voltage-dependent anion channel 1 (VDAC1), the calcium intake channel of mitochondria, in the PFOS-cultured cells. Moreover, we found that ATP synthase F1 subunit beta (ATP5B) interacted with TRPML1 and VDAC1 in the L-02 cells and the liver of mice under PFOS exposure. Inhibiting ATP5B expression or restraining the ATP5B on the plasma membrane reduced the interplay between TRPML1 and VDAC1, reversed the mitochondrial calcium overload and deteriorated the lysosomal calcium accumulation in the PFOS-cultured cells. Our research unveils the molecular regulation of the calcium crosstalk between lysosomes and mitochondria, and explains PFOS-induced IR in the context of activated autophagy.
摘要：
全氟辛烷磺酸(PFOS)，官方列出的持久性有机污染物，是一种广泛分布的全氟烷基物质。流行病学研究表明，全氟辛烷磺酸与胰岛素抵抗（IR）的发生密切相关。然而,详细的机制仍然模糊。在以往的研究中,我们发现线粒体钙超载与PFOS诱导的肝脏IR有关。在这项研究中,我们发现全氟辛烷磺酸暴露显著提高溶酶体钙在L-02肝细胞从0.5小时。在全氟辛烷磺酸培养的L-02细胞，抑制自噬减轻溶酶体钙超载。线粒体钙摄取的抑制加剧了溶酶体钙的积累，而抑制溶酶体钙的流出逆转了PFOS诱导的线粒体钙超载和IR。瞬时受体电位粘磷脂1（TRPML1），溶酶体的钙输出通道，与电压依赖性阴离子通道1(VDAC1)相互作用，线粒体的钙摄入通道，在全氟辛烷磺酸培养的细胞中。此外，我们发现ATP合酶F1亚基β(ATP5B)在全氟辛烷磺酸暴露下的L-02细胞和小鼠肝脏中与TRPML1和VDAC1相互作用.抑制ATP5B表达或抑制ATP5B在质膜上减少了TRPML1和VDAC1之间的相互作用，逆转了线粒体钙超载，并恶化了PFOS培养细胞中溶酶体钙的积累。我们的研究揭示了溶酶体和线粒体之间钙串扰的分子调控，并解释了在激活的自噬背景下全氟辛烷磺酸诱导的IR。
