期刊
SCIENCE OF THE TOTAL ENVIRONMENT
卷 825, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.scitotenv.2022.153933
关键词
Perfluorooctane sulfonate; Autophagy; Mitochondrial calcium; Detyrosinated alpha-tubulin; Insulin resistance
资金
- National Natural Science Foundation of China [81602881]
- China Postdoctoral Science Foundation [2018T110226, 2017M611239]
This study found that PFOS causes insulin resistance by promoting autophagy and mitochondrial calcium accumulation. The study also identified detyrosinated alpha-tubulin as a key component connecting autophagy and mitochondrial calcium response.
Y Perfluorooctane sulfonate (PFOS), one kind of persistent organic pollutants, is associated with insulin resistance (IR) in general population. However, the exact mechanism is still obscure. In this study, we found that 50 mu M PFOS caused IR in L-02 hepatocytes after 1 h, and induced autophagy and mitochondrial calcium (Ca2+) accumulation as early as 0.5 h. Inhibiting autophagy relieved mitochondrial Ca2+ overload and then reversed IR. Mitochondria were aggregated at cell periphery, and extracellular Ca2+ from IP3R2 on the plasma membrane, rather than endoplasmic reticulum Ca2+, was the priority source of mitochondrial Ca2+ uptake at early stages of PFOS exposure. Furthermore, we discovered that the linkage connecting autophagy and mitochondrial Ca2+ response was detyrosinated alpha-tubulin, which autophagy-dependently ascended, interacted with VDAC1 and enhanced the formation of IP3R2-VDAC1-MICU1 complex. Consistently, PFOS caused IR, activated autophagy, induced mitochondrial Ca2+ overload, increased the level of detyrosinated alpha-tubulin, and promoted the formation of IP3R2-VDAC1-MICU1 complex in the liver of C57BL/6J mice exposed to 2.5 mg/kg/day PFOS for 6 weeks. This study clarified that autophagy and mitochondrial Ca2+ accumulation were the early and triggering event that caused PFOS-related IR, also unveiled a novelmechanism regulating mitochondrial Ca2+ homeostasis.
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