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Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase‐II
Author(s) -
Miyamoto Shigeki,
Murphy Anne N.,
Brown Joan Heller
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.1017.9
Subject(s) - protein kinase b , mitochondrial permeability transition pore , phosphorylation , mitochondrion , microbiology and biotechnology , pi3k/akt/mtor pathway , cytochrome c , voltage dependent anion channel , depolarization , chemistry , biology , programmed cell death , apoptosis , biochemistry , signal transduction , biophysics , escherichia coli , bacterial outer membrane , gene
Akt activation supports survival of cardiomyocytes against cell death through opening of the mitochondrial permeability transition pore (PT‐pore). Mitochondrial depolarization induced by H 2 0 2 is prevented by activation of Akt with leukemia inhibitory factor (LIF). This protective effect is observed even when cardiomyocytes treated with LIF are permeabilized and mitochondrial depolarization is elicited by elevating Ca 2+ . Cell fractionation studies demonstrate that LIF treatment increases both total and phosphorylated Akt in the mitochondrial fraction and that mitochondrial Akt associates with hexokinase‐II (HK‐II). HK‐II contains consensus sequences for phosphorylation by Akt and LIF treatment induces PI3K‐ and Akt‐dependent HK‐II phosphorylation. Addition of recombinant active Akt to adult mouse heart mitochondria directly stimulates phosphorylation of HK‐II and concomitantly inhibits the ability of Ca 2+ to induce cytochrome‐c release; this effect of Akt is prevented when HK‐II is dissociated from mitochondria by incubation with glucose 6‐phosphate or HK‐II dissociating peptide. Finally LIF stabilizes HK‐II association with mitochondria and requires mitochondrial HK‐II to mediate cardiomyocyte protection. We conclude that Akt protects against oxidant or Ca 2+ ‐stimulated PT‐pore opening through a direct effect at the mitochondria mediated via phosphorylation of mitochondrial HK‐II. AHA Beginning Grant in Aide (Shigeki Miyamoto); NIH PPG 82521