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Metabolic Control of Cell Death : The Role of Bcl‐xL
Author(s) -
Park HanA,
Licznerski Pawel,
Niu Yulong,
Mnatsakanyan Nelli,
Miranda Paige,
Wu Jing,
Sacchetti Silvio,
Polster Brian M,
Alavian Kambiz N,
Jonas Elizabeth A
Publication year - 2016
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.30.1_supplement.1162.2
Subject(s) - bcl xl , programmed cell death , glutamate receptor , excitotoxicity , mitochondrial permeability transition pore , mitochondrion , neuroprotection , apoptosis , microbiology and biotechnology , biology , chemistry , biochemistry , pharmacology , receptor
B‐cell lymphoma‐extra large (Bcl‐xL) protein is an anti‐apoptotic member of the Bcl2 family. In contrast to its protective functions, Bcl‐xL is also capable of playing a pro‐apoptotic role. ΔN‐Bcl‐xL, the C‐terminal cleavage product of Bcl‐xL, is produced during brain ischemia and activates large conductance mitochondrial channel activity. We hypothesized that regulation of ΔN‐Bcl‐xL activity or levels is critical for neuronal survival or death. We achieved ΔN‐Bcl‐xL potentiation or arrest by using different concentrations of ABT‐737, a specific small molecule inhibitor of Bcl‐xL. We further investigated how ΔN‐Bcl‐xL could regulate neuronal energy metabolism by interaction with the mitochondrial ATP synthase. In this study, we find that a high concentration of ABT‐737 (1μM) blocks the effects of full length Bcl‐xL but a low concentration of ABT‐737 (10 nM) inhibits ΔN‐Bcl‐xL. We tested whether ABT‐737 exerts neuroprotective properties by altering mitochondrial membrane permeability during cell death stimuli. We found that ΔN‐Bcl‐xL levels are enhanced after glutamate‐induced excitotoxicity. Pre‐treatment of neurons with 1μM ABT‐737 aggravated glutamate‐induced death. We observed a loss of mitochondrial potential and a decline in ATP production in high ABT‐737 and glutamate treated cells. In contrast, pre‐treatment with 10nM ABT‐737, a hundred fold lower concentration, rescued neurons from death and augmented mitochondrial potential and ATP production similarly to effects of Cyclosporine A (CsA) during glutamate challenge. Incubation of recombinant ΔN‐Bcl‐xL protein with isolated mitochondria significantly reduced mitochondrial potential, rescued by CsA or low ABT‐737. This suggests involvement of the mitochondrial permeability transition pore (mPTP), the relative closure of which may improveneuronal survival. To confirm this, we depleted the c‐subunit of the ATP synthase, the putative mPTP. We found that c‐subunit depletion is neuroprotective against the metabolic death‐inducing effect of ΔN‐Bcl‐xL in glutamate‐exposed neurons. Our findings suggest that low concentrations of Bcl‐xL inhibitors may promote survival by preferentially binding to the pro‐apoptotic form of Bcl‐xL even as high concentrations potentiate cell death in malignant cells and in neurons. Support or Funding Information NIH NS04587