title: Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential.
abstract: Mammalian Bcl-x(L) protein localizes to the outer mitochondrial membrane, where it inhibits apoptosis by binding Bax and inhibiting Bax-induced outer membrane permeabilization. Contrary to expectation, we found by electron microscopy and biochemical approaches that endogenous Bcl-x(L) also localized to inner mitochondrial cristae. Two-photon microscopy of cultured neurons revealed large fluctuations in inner mitochondrial membrane potential when Bcl-x(L) was genetically deleted or pharmacologically inhibited, indicating increased total ion flux into and out of mitochondria. Computational, biochemical, and genetic evidence indicated that Bcl-x(L) reduces futile ion flux across the inner mitochondrial membrane to prevent a wasteful drain on cellular resources, thereby preventing an energetic crisis during stress. Given that F(1)F(O)-ATP synthase directly affects mitochondrial membrane potential and having identified the mitochondrial ATP synthase β subunit in a screen for Bcl-x(L)-binding partners, we tested and found that Bcl-x(L) failed to protect β subunit-deficient yeast. Thus, by bolstering mitochondrial energetic capacity, Bcl-x(L) may contribute importantly to cell survival independently of other Bcl-2 family proteins.
authors: Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors: Ying-Bei
authors: YB
authors: Chen
authors: Miguel A
authors: MA
authors: Aon
authors: Yi-Te
authors: YT
authors: Hsu
authors: Lucian
authors: L
authors: Soane
authors: Xinchen
authors: X
authors: Teng
authors: J Michael
authors: JM
authors: McCaffery
authors: Wen-Chih
authors: WC
authors: Cheng
authors: Bing
authors: B
authors: Qi
authors: Hongmei
authors: H
authors: Li
authors: Kambiz N
authors: KN
authors: Alavian
authors: Margaret
authors: M
authors: Dayhoff-Brannigan
authors: Shifa
authors: S
authors: Zou
authors: Fernando J
authors: FJ
authors: Pineda
authors: Brian
authors: B
authors: O'Rourke
authors: Young H
authors: YH
authors: Ko
authors: Peter L
authors: PL
authors: Pedersen
authors: Leonard K
authors: LK
authors: Kaczmarek
authors: Elizabeth A
authors: EA
authors: Jonas
authors: J Marie
authors: JM
authors: Hardwick
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D004734:Energy Metabolism; D005656:Fungal Proteins; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008928:Mitochondria; D051336:Mitochondrial Membranes / Q000378:metabolism*; D009474:Neurons; D051020:bcl-X Protein / Q000172:deficiency / Q000502:physiology*
chemical_list: D005656:Fungal Proteins; D051020:bcl-X Protein