The lignan manassantin is a potent and specific inhibitor of mitochondrial complex I and bioenergetic activity in mammals [Metabolism]

Dineolignans manassantin A and B from the plant Saururus cernuus are used in traditional medicine to manage a wide range of ailments such as edema, jaundice, and gonorrhea. Cell-based studies have identified several molecular target candidates of manassantin including NF-kappaB, MAPK, STAT3 and hypoxia-inducible factor 1 alpha (HIF-1alpha). It is unclear whether or how these structurally diverse proteins or pathways mediate any of the medical benefits of manassantin in vivo. Moreover, it has been recently reported that manassantin causes developmental arrest in zebrafish by inhibiting the mitochondrial complex I, but it is unknown whether manassantin inhibits mitochondrial respiration in intact mammalian cells and live animals. Here, we present direct evidence that manassantin potently and specifically inhibits the mitochondrial complex I and bioenergetic activity in mammalian systems. Manassantin had no effect on complex II- or complex IV-mediated respiration. Of note, it decreased NADH-ubiquinone reductase activity but not that of NADH-ferricyanide reductase. Treatment with manassantin reduced cellular ATP levels and concomitantly stimulated AMP-activated protein kinase (AMPK) in vitro and in vivo. As an adaptive response to manassantin-induced bioenergetic deficiency, mammalian cells upregulated aerobic glycolysis, a process mediated by AMPK independent of HIF-1alpha. These results together demonstrate a biologically important activity of manassantin in the control of complex I-mediated respiration and its profound effects on oxygen utilization, energy homeostasis and glucose metabolism in mammalian cells.

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