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O‐GlcNAc signaling attenuates mitochondrial permeability transition
Author(s) -
Ngoh Gladys Afor,
Jones Steven P
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1130.8
Subject(s) - voltage dependent anion channel , cardioprotection , mitochondrion , mitochondrial permeability transition pore , chemistry , mptp , microbiology and biotechnology , biochemistry , biophysics , endocrinology , medicine , apoptosis , bacterial outer membrane , ischemia , biology , dopaminergic , escherichia coli , programmed cell death , gene , dopamine
We have shown that glycosylation of proteins with O ‐linked β‐N‐acetylglucosamine ( O ‐GlcNAc) preserves mitochondrial membrane potential, attenuates post‐hypoxic injury, and reduces myocardial infarct size in vivo . Based on our recent identification of voltage dependent anion channel (VDAC) as an O ‐GlcNAc modified protein, we hypothesized that O ‐GlcNAc signaling mediates cardioprotection by attenuating sensitivity to mPTP formation. Here, isolated cardiac mitochondria from Vehicle‐ (normal O ‐GlcNAc), PUGNAc‐ (high O ‐GlcNAc; 50mg/kg, 18hours), or TT04‐treated (low O ‐GlcNAc; 10mg/kg, 18hours) C57BL/6J mice showed no difference in total VDAC levels (n>/=3/group). for O ‐GlcNAc and immunoblot for VDAC (n>/=3/group), and vice versa, revealed a significant increase in O ‐ GlcNAc modified VDAC for cardiac mitochondria from high O ‐GlcNAc mice with Vehicle, while a significant reduction of O ‐GlcNAc‐modified VDAC was observed with cardiac mitochondria from low O ‐GlcNAc mice compared to Vehicle. To assess functional effects of changes in O ‐GlcNAc modification of VDAC on mPTP formation, cardiac mitochondria from high, normal, and low O ‐GlcNAc mice were challenged with 100μM CaCl 2 and the decrease in spectrohotometric absorbance recorded as an index of mitochondrial swelling. Mitochondria from high O ‐GlcNAc mice were significantly less sensitive to calcium‐induced swelling, those from low O ‐GlcNAc mice were more sensitive to calcium‐induced swelling compared with Vehicle. We that prevention of mPTP formation, potentially via O ‐GlcNAc modification of VDAC, represents a novel mechanism of cardioprotection. NIH (HL0833220), AHA (0535270N) and AHA (0715493B).