Autophagy-dependent lysosomal calcium overload and the ATP5B-regulated lysosomes-mitochondria calcium transmission induce liver insulin resistance under perfluorooctane sulfonate exposure

• Published in: Ecotoxicology and environmental safety 2024-05, Vol.276, p.116318-116318, Article 116318
• Main Authors: Li, Jixun, Ma, Yu, Qiu, Tianming, Wang, Jianyu, Zhang, Jingyuan, Sun, Xiance, Jiang, Liping, Li, Qiujuan, Yao, Xiaofeng
• Format: Article
• Language: English
• Subjects: ATP synthase F1 subunit beta; Insulin resistance; Lysosomal calcium; Mitochondrial calcium; Perfluorooctane sulfonate
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2024.116318

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. [Display omitted] •Autophagy induces lysosomal calcium overload under PFOS exposure.•The release of overloaded lysosomal calcium causes hepatic IR upon PFOS exposure.•TRPML1 interacts with VDAC1 under PFOS exposure.•ATP5B interacts with TRPML1 and VDAC1, and regulates TRPML1-VDAC1 interaction.•Plasma-membrane ATP5B regulates the lysosomes-mitochondria calcium transmission.