PFOS causes lysosomes-regulated mitochondrial fission through TRPML1-VDAC1 and oligomerization of MCU/ATP5J2 by Wei Yang instant download

PFOS causes lysosomes-regulated mitochondrial fission through TRPML1-VDAC1 and oligomerization of MCU/ATP5J2 by Wei Yang instant download

ABSTRACTKeywords:Perfluorooctane sulfonate (PFOS), a listed persistent organic pollutant, poses risks to human health and is closely Perfluorooctane sulfonatelinked to chronic metabolic diseases. Although the role of mitochondrial fission in these diseases has garnered Toxicity mechanismattention, whether and how PFOS induces mitochondrial fission remains obscure. Here, we found that PFOS ATP synthaseinduced mitochondrial fission, as demonstrated by the fragmentation of mitochondria and the upregulation of dynamin-related protein 1 (DRP1), phospho-DRP1 and mitochondrial fission protein 1 (FIS1) in human hepatocytes MIHA and mice liver. Blocking the calcium transfer from lysosomes to mitochondria that was executed by transient receptor potential mucolipin 1 (TRPML1) of lysosomes and voltage-dependent anion channel 1 (VDAC1) of mitochondria, did not affect PFOS-induced mitochondrial fission. In contrast, knockdown of TRPML1 or VDAC1 reversed this process. Knockdown of mitochondrial calcium uniporter (MCU), rather than inhibiting its activity, effectively alleviated PFOS-induced mitochondrial fission. Additionally, PFOS increased MCU oligomers without affecting MCU monomer. Inhibiting autophagy reversed the MCU oligomerization. Further investigation unveiled the interactions of MCU with VDAC1, TRPML1, mitochondrial Fo complex subunit F2 (ATP5J2) and DRP1 in PFOS-exposed mice liver and MIHA cells. We also discovered that knockdown of ATP5J2 alleviated PFOS-induced mitochondrial fission. Ulteriorly, PFOS upregulated ATP5J2 that underwent oligomerization. Knockdown of MCU reversed the increase in ATP5J2. Our study uncovers the presence and molecular basics of