title: Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase.
abstract: Anti-apoptotic Bcl2 family proteins such as Bcl-x(L) protect cells from death by sequestering apoptotic molecules, but also contribute to normal neuronal function. We find in hippocampal neurons that Bcl-x(L) enhances the efficiency of energy metabolism. Our evidence indicates that Bcl-x(L)interacts directly with the β-subunit of the F(1)F(O) ATP synthase, decreasing an ion leak within the F(1)F(O) ATPase complex and thereby increasing net transport of H(+) by F(1)F(O) during F(1)F(O) ATPase activity. By patch clamping submitochondrial vesicles enriched in F(1)F(O) ATP synthase complexes, we find that, in the presence of ATP, pharmacological or genetic inhibition of Bcl-x(L) activity increases the membrane leak conductance. In addition, recombinant Bcl-x(L) protein directly increases the level of ATPase activity of purified synthase complexes, and inhibition of endogenous Bcl-x(L) decreases the level of F(1)F(O) enzymatic activity. Our findings indicate that increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl-x(L)-expressing neurons.
authors.affiliation: Department of Internal Medicine, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Kambiz N
authors.initials: KN
authors.lastname: Alavian
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Leon
authors.initials: L
authors.lastname: Collis
authors.forename: Laura
authors.initials: L
authors.lastname: Bonanni
authors.forename: Lu
authors.initials: L
authors.lastname: Zeng
authors.forename: Silvio
authors.initials: S
authors.lastname: Sacchetti
authors.forename: Emma
authors.initials: E
authors.lastname: Lazrove
authors.forename: Panah
authors.initials: P
authors.lastname: Nabili
authors.forename: Benjamin
authors.initials: B
authors.lastname: Flaherty
authors.forename: Morven
authors.initials: M
authors.lastname: Graham
authors.forename: Yingbei
authors.initials: Y
authors.lastname: Chen
authors.forename: Shanta M
authors.initials: SM
authors.lastname: Messerli
authors.forename: Maria A
authors.initials: MA
authors.lastname: Mariggio
authors.forename: Christoph
authors.initials: C
authors.lastname: Rahner
authors.forename: Ewan
authors.initials: E
authors.lastname: McNay
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Shore
authors.forename: Peter J S
authors.initials: PJ
authors.lastname: Smith
authors.forename: J Marie
authors.initials: JM
authors.lastname: Hardwick
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Jonas
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D006868:Hydrolysis; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D051336:Mitochondrial Membranes / Q000201:enzymology; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D009596:Nitrophenols / Q000494:pharmacology; D009840:Oligomycins / Q000494:pharmacology; D010101:Oxygen Consumption; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology; D061209:Proton Ionophores / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000201:enzymology*; D013997:Time Factors; D014162:Transfection; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C501332:ABT-737; C494774:Bak1 protein, rat; C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D009840:Oligomycins; D010879:Piperazines; D061209:Proton Ionophores; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000255:Adenosine Triphosphate; D025261:Mitochondrial Proton-Translocating ATPases