The Natural Antioxidant Otobaphenol Delays the Permeability Transition of Mitochondria and Induces Their Aggregation

The lignan otobaphenol, (8R,8′R,7R)-4′-hydroxy-5′-methoxy-3,4-methylenedioxy-2′,7,8,8′-neolignan, extracted from Virola Aff. Pavonis leaves, completely inhibits at a concentration of 2.5 µM the Fe³⁺-ascorbate-induced lipoperoxidation of rat liver mitochondria that was determined by oxygen consumption and accumulation of thiobarbituric acid-reactive species. At 25 µM, it delays the mitochondrial permeability transition induced by tert-butyl hydroperoxide or Ca²⁺, substantially inhibits the state 3 respiration, does not affect the state 4 respiration and the ADP/O ratio (with succinate), diminishes the rate of Ca²⁺ uptake by mitochondria, and delays the ruthenium red-insensitive uncoupler-induced release of the loaded Ca²⁺. Dose-dependent delaying of the calcium-induced swelling of mitochondria in the presence of otobaphenol nonlinearly correlates with its 1,1-diphenyl-2-picrylhydrazyl free radical scavenging activity. At 75 µM and higher, this lignan causes mitochondrial aggregation and is able to aggregate itself, without mitochondria. The formed aggregates of otobaphenol do not cause an aggregation of subsequently added mitochondria. Thus, otobaphenol seems to be a promising target to prevent the oxidative stress death of cells.