Melatonin preserves the transient mitochondrial permeability transition for protection during mitochondrial Ca2+ stress in astrocyte

Abstract

Cells have two modes of mitochondrial permeability transition (MPT) which produce virtually opposite pathophysiological outcomes of survival or death when responding to apoptotic insults. The transient-MPT (t-MPT) protects mitochondria, whereas the prolonged-MPT (p-MPT), once activated, triggers the 'point of no return' for apoptosis or necrosis. Our previous studies show that in addition to scavenging mitochondrial reactive oxygen species, melatonin targets mitochondrial Ca(2+) (mCa(2+))-mediated MPT for protection during mCa(2+)-mediated apoptosis in astrocytes. The precise mechanism for how melatonin modulates the MPT during mCa(2+) stress, however, remains unelucidated. With the application of fluorescence laser scanning imaging microscopy, this study demonstrated for the first time that melatonin does not inhibit the MPT pore, rather it crucially preserves the pore in its protective mode of t-MPT during mCa(2+) stress. Melatonin-preserved t-MPT importantly maintained mitochondrial membrane potential (ΔΨ(m)) which not only prevented depolarized ΔΨ(m)-induced p-MPT but also retained ΔΨ(m)-dependent ATP formation during disturbed Ca(2+) homeostasis. Additionally, the melatonin-preserved t-MPT allowed mitochondria to release the toxic overload of mCa(2+) to sublethal levels, which prevented mCa(2+)-mediated fission and mCa(2+)-dependent p-MPT and possibly also improved mCa(2+)-dependent ATP synthesis. Melatonin's effect in reducing the Ca(2+) load greatly diminished when the MPT was inhibited by cyclosporine A, suggesting its pore dependency as well as that a preserved t-MPT may be superior to a MPT inhibition in protecting mCa(2+)-mediated apoptosis. The unique modulation on the MPT provided by melatonin may have extraordinary therapeutic potential in the treatment of mCa(2+)-mediated astrocyte-associated neurodegenerative pathologies and diseases.