The neurotoxic secreted phospholipase A(2) from the Vipera a. ammodytes venom targets cytochrome c oxidase in neuronal mitochondria

The β-neurotoxic secreted phospholipases A(2) (sPLA(2)s) block neuro-muscular transmission by poisoning nerve terminals. Damage inflicted by such sPLA(2)s (β-ntx) on neuronal mitochondria is characteristic, very similar to that induced by structurally homologous endogenous group IIA sPLA(2) when its activity is elevated, as, for example, in the early phase of Alzheimer’s disease. Using ammodytoxin (Atx), the β-ntx from the venom of the nose-horned viper (Vipera a. ammodytes), the sPLA(2) receptor R25 has been detected in neuronal mitochondria. This receptor has been purified from porcine cerebral cortex mitochondria by a new Atx-affinity-based chromatographic procedure. Mass spectrometry analysis revealed R25 to be the subunit II of cytochrome c oxidase (CCOX), an essential constituent of the respiratory chain complex. CCOX was confirmed as being the first intracellular membrane receptor for sPLA(2) by alternative Atx-affinity-labellings of purified CCOX, supported also by the encounter of Atx and CCOX in PC12 cells. This discovery suggests the explanation of the mechanism by which β-ntx hinders production of ATP in poisoned nerve endings. It also provides a new insight into the potential function and dysfunction of endogenous GIIA sPLA(2) in mitochondria.