Abstract
FTY-720 (Fingolimod) was one of the first compounds authorized for the treatment of multiple sclerosis. Among its other activities, this sphingosine analogue enhances exocytosis in neuroendocrine chromaffin cells, altering the quantal release of catecholamines. Surprisingly, the size of chromaffin granules is reduced within few minutes of treatment, a process that is paralleled by the homotypic fusion of granules and their heterotypic fusion with mitochondria, as witnessed by dynamic confocal and TIRF microscopy. Electron microscopy studies support these observations, revealing the fusion of several vesicles with individual mitochondria to form large, round mixed organelles. This cross-fusion is SNARE-dependent, being partially prevented by the expression of an inactive form of SNAP-25. Fused mitochondria exhibit an altered redox potential, which dramatically enhances cell death. Therefore, the cross-fusion of intracellular organelles appears to be a new mechanism to be borne in mind when considering the effect of FTY-720 on the survival of neuroendocrine cells.
Highlights
The exocytotic fusion of vesicles with the plasma membrane is a fundamental event in neuronal and endocrine systems, facilitating the release of active substances like neurotransmitters and hormones
Among the drugs derived from the structure of signalling lipids, FTY-720 is an analogue of sphingosine that has been used extensively to produce immunosuppression[22] and as such, it has been approved for the treatment of MS12
Chromaffin cells in culture were stimulated by depolarization with a high KCl buffer and their secretory activity was studied by amperometry[25,26]
Summary
The exocytotic fusion of vesicles with the plasma membrane is a fundamental event in neuronal and endocrine systems, facilitating the release of active substances like neurotransmitters and hormones. More evidence appeared in recent years suggesting that this compound accumulates in cells of the CNS, modulating the activity of neurons and astrocytes[14,15], potentially making it suitable to treat a variety of neurological syndromes like ischemia, stroke and neurodegeneration[16,17,18]. This drug has been proposed for the treatment of neuronal cancers given its potential to induce the death of neuroblastoma cells[19]. Our results show that FTY-720 affects www.nature.com/scientificreports secretory process and, it induces the homotypic and heterotypic fusion of organelles in the cytosol, impairing mitochondrial function and provoking cell death
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