Perfluorooctane sulfonate induces mitochondrial calcium overload and early hepatic insulin resistance via autophagy/detyrosinated alpha-tubulin-regulated IP3R2-VDAC1-MICU1 interaction.

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 µM 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 α-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 α-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 novel mechanism regulating mitochondrial Ca2+ homeostasis.