2025/07/25 by Valerie I. C. Rebhahn, Mohamad Saoud, Mathias Winterhalter +10 · 1 voice
Biochemistry, Genetics and Molecular Biology · #Mitochondrial Function and Pathology #Metabolomics and Mass Spectrometry Studies #ATP Synthase and ATPases Research
paper · pdf · doi:10.1021/acs.chemrestox.5c00147
openalex publication_date 2025/07/25 · openalex created_date 2025/10/10 · openalex updated_date 2026/06/22
High Resolution Image Download MS PowerPoint Slide Aetokthonotoxin (AETX) is an emerging environmental toxin produced by the freshwater cyanobacterium Aetokthonos hydrillicola . Accumulating in the food chain, it causes vacuolar myelinopathy, a neurological disease affecting a wide range of wildlife characterized by the development of large intramyelinic vacuoles in the white matter of the brain. So far, the mode of action of AETX is unknown. After discovering that AETX is cytostatic and arrests cancer cell lines in the G 1 phase, metabolomic profiling of AETX-treated cells as well as an assessment of the physicochemical properties of the compound suggested that AETX is a weakly acidic uncoupler of mitochondrial respiration. We confirmed this hypothesis by in vitro assays on mammalian cells, finding that AETX has the expected effects on mitochondrial network morphology, mitochondrial membrane potential, and oxygen consumption rate, resulting in affected ATP generation. We confirmed that AETX is capable of transporting protons across lipid bilayers. In summary, we demonstrate that AETX is a protonophore that uncouples oxidative phosphorylation in mitochondria, which is the primary event of AETX intoxication.