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Protective stabilization of mitochondrial permeability transition and mitochondrial oxidation during mitochondrial Ca 2+ stress by melatonin's cascade metabolites C3‐OHM and AFMK in RBA1 astrocytes
Author(s) -
Jou MeiJie,
Peng TsungI,
Reiter Russel J.
Publication year - 2019
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12538
Subject(s) - mitochondrion , oxidative stress , mitochondrial permeability transition pore , melatonin , antioxidant , membrane potential , microbiology and biotechnology , chemistry , reactive oxygen species , biophysics , biology , biochemistry , programmed cell death , apoptosis , neuroscience
Cyclic 3‐hydroxymelatonin (C3‐OHM) and N 1‐acetyl‐ N 2‐formyl‐5‐methoxykynuramine (AFMK) are two major cascade metabolites of melatonin. We previously showed melatonin provides multiple levels of mitochondria‐targeted protection beyond as a mitochondrial antioxidant during ionomycin‐induced mitochondrial Ca 2+ (mCa 2+ ) stress in RBA1 astrocytes. Using noninvasive laser scanning fluorescence coupled time‐lapse digital imaging microscopy, this study investigated whether C3‐OHM and AFMK also provide mitochondrial levels of protection during ionomycin‐induced mCa 2+ stress in RBA1 astrocytes. Interestingly, precise temporal and spatial dynamic live mitochondrial images revealed that C3‐OHM and AFMK prevented specifically mCa 2+ ‐mediated mitochondrial reactive oxygen species (mROS) formation and hence mROS‐mediated depolarization of mitochondrial membrane potential (△Ψ m ) and permanent lethal opening of the MPT (p‐MPT). The antioxidative effects of AFMK, however, were less potent than that of C3‐OHM. Whether C3‐OHM and AFMK targeted directly the MPT was investigated under a condition of “oxidation free‐Ca 2+ stress” using a classic antioxidant vitamin E to remove mCa 2+ ‐mediated mROS stress and the potential antioxidative effects of C3‐OHM and AFMK. Intriguingly, two compounds still effectively postponed “oxidation free‐Ca 2+ stress”‐mediated depolarization of △Ψ m and p‐MPT. Measurements using a MPT pore‐specific indicator Calcein further identified that C3‐OHM and AFMK, rather than inhibiting, stabilized the MPT in its transient protective opening mode (t‐MPT), a critical mechanism to reduce overloaded mROS and mCa 2+ . These multiple layers of mitochondrial protection provided by C3‐OHM and AFMK thus crucially allow melatonin to extend its metabolic cascades of mitochondrial protection during mROS‐ and mCa 2+ ‐mediated MPT‐associated apoptotic stresses and may provide therapeutic benefits against astrocyte‐mediated neurodegeneration in the CNS.