F-53B disrupts energy metabolism by inhibiting the V-ATPase-AMPK axis in neuronal cells

Area of Science:

• Neuroscience
• Toxicology
• Cell Biology

Background:

• 6:2 chloro-polyfluorooctane ether sulfonate (F-53B) is a suspected neurotoxin.
• The precise mechanisms of F-53B neurotoxicity, particularly concerning energy metabolism, are not well understood.

Purpose of the Study:

• To investigate the neurotoxic effects of F-53B on neuronal cells.
• To elucidate the role of the V-ATPase-AMPK axis in F-53B-induced abnormal energy metabolism.

Main Methods:

• Utilized mouse astrocytes (C8-D1A) and human neuroblastoma cells (SH-SY5Y) as in vitro models.
• Exposed cells to F-53B and analyzed V-ATPase activity, lysosomal function, AMPK signaling, mitochondrial function, and key metabolic proteins.
• Investigated the effects of resveratrol, an AMPK agonist, on F-53B-treated cells.

Main Results:

• F-53B inhibited V-ATPase B2 expression and activity, increasing lysosomal pH and disrupting calcium homeostasis.
• This led to reduced CaMKK2 and phosphorylated AMPK (p-AMPK) levels, causing mitochondrial damage and impaired oxidative phosphorylation.
• F-53B decreased the expression of glycolytic enzyme PFKFB3; V-ATPase B2 overexpression activated AMPK.
• Resveratrol treatment ameliorated mitochondrial dysfunction and enhanced ATP production.

Conclusions:

• F-53B induces neurotoxicity through a novel V-ATPase-AMPK axis pathway, disrupting neuronal energy metabolism.
• Mitochondrial dysfunction and impaired glycolysis are key consequences of F-53B exposure.
• V-ATPase and AMPK represent potential therapeutic targets for mitigating F-53B neurotoxicity.