Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase
Kambiz N. Alavian,Hongmei Li,Leon P. Collis,Laura Bonanni,Lu Zeng,Silvio Sacchetti,Emma Lazrove,Panah Nabili,Benjamin J. Flaherty,Morven Graham,Ying Bei Chen,Shanta M. Messerli,Maria A. Mariggiò,Christopher Rahner,Ewan C. McNay,Gordon C. Shore,Peter K. Smith,Peter K. Smith,J. Marie Hardwick,Elizabeth A. Jonas +19 more
TLDR
It is found in hippocampal neurons that Bcl-xL enhances the efficiency of energy metabolism and increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl/xL-expressing neurons.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.read more
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Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.
Lorenzo Galluzzi,Lorenzo Galluzzi,Ilio Vitale,Stuart A. Aaronson,John M. Abrams,Dieter Adam,Patrizia Agostinis,Emad S. Alnemri,Lucia Altucci,Ivano Amelio,David W. Andrews,David W. Andrews,Margherita Annicchiarico-Petruzzelli,Alexey V. Antonov,Eli Arama,Eric H. Baehrecke,Nickolai A. Barlev,Nicolas G. Bazan,Francesca Bernassola,Mathieu J.M. Bertrand,Katiuscia Bianchi,Mikhail V. Blagosklonny,Klas Blomgren,Christoph Borner,Patricia Boya,Catherine Brenner,Catherine Brenner,Michelangelo Campanella,Eleonora Candi,Didac Carmona-Gutierrez,Francesco Cecconi,Francis Ka-Ming Chan,Navdeep S. Chandel,Emily H. Cheng,Jerry E. Chipuk,John A. Cidlowski,Aaron Ciechanover,Gerald M. Cohen,Marcus Conrad,Juan R. Cubillos-Ruiz,Peter E. Czabotar,Peter E. Czabotar,Vincenzo D'Angiolella,Ted M. Dawson,Valina L. Dawson,Vincenzo De Laurenzi,Ruggero De Maria,Klaus-Michael Debatin,Ralph J. DeBerardinis,Mohanish Deshmukh,Nicola Di Daniele,Francesco Di Virgilio,Vishva M. Dixit,Scott J. Dixon,Colin S. Duckett,Brian David Dynlacht,Wafik S. El-Deiry,John W. Elrod,Gian Maria Fimia,Simone Fulda,Simone Fulda,Ana J. García-Sáez,Abhishek D. Garg,Carmen Garrido,Carmen Garrido,Evripidis Gavathiotis,Pierre Golstein,Eyal Gottlieb,Eyal Gottlieb,Douglas R. Green,Lloyd A. Greene,Hinrich Gronemeyer,Atan Gross,György Hajnóczky,J. Marie Hardwick,Isaac S. Harris,Michael O. Hengartner,Claudio Hetz,Hidenori Ichijo,Marja Jäättelä,Bertrand Joseph,Philipp J. Jost,Philippe Juin,William J. Kaiser,Michael Karin,Thomas Kaufmann,Oliver Kepp,Adi Kimchi,Richard N. Kitsis,Daniel J. Klionsky,Richard A. Knight,Sharad Kumar,Sam W. Lee,John J. Lemasters,Beth Levine,Andreas Linkermann,Stuart A. Lipton,Richard A. Lockshin,Richard A. Lockshin,Carlos López-Otín,Scott W. Lowe,Scott W. Lowe,Tom Luedde,Enrico Lugli,Marion MacFarlane,Frank Madeo,Michal Malewicz,Walter Malorni,Gwenola Manic,Jean-Christophe Marine,Seamus J. Martin,Jean-Claude Martinou,Jan Paul Medema,Patrick Mehlen,Pascal Meier,Sonia Melino,Edward A. Miao,Jeffery D. Molkentin,Ute M. Moll,Cristina Muñoz-Pinedo,Shigekazu Nagata,Gabriel Núñez,Andrew Oberst,Moshe Oren,Michael Overholtzer,Michele Pagano,Theocharis Panaretakis,Theocharis Panaretakis,Manolis Pasparakis,Josef M. Penninger,David M. Pereira,Shazib Pervaiz,Marcus E. Peter,Mauro Piacentini,Paolo Pinton,Jochen H. M. Prehn,Hamsa Puthalakath,Gabriel A. Rabinovich,Markus Rehm,Rosario Rizzuto,Cecília M. P. Rodrigues,David C. Rubinsztein,Thomas Rudel,Kevin M. Ryan,Emre Sayan,Luca Scorrano,Feng Shao,Yufang Shi,Yufang Shi,John Silke,John Silke,Hans-Uwe Simon,Antonella Sistigu,Brent R. Stockwell,Andreas Strasser,Gyorgy Szabadkai,Gyorgy Szabadkai,Gyorgy Szabadkai,Stephen W.G. Tait,Daolin Tang,Daolin Tang,Nektarios Tavernarakis,Andrew Thorburn,Yoshihide Tsujimoto,Boris Turk,Tom Vanden Berghe,Peter Vandenabeele,Matthew G. Vander Heiden,Matthew G. Vander Heiden,Andreas Villunger,Herbert W. Virgin,Karen H. Vousden,Domagoj Vucic,Erwin F. Wagner,Henning Walczak,David Wallach,Ying Wang,James A. Wells,Will Wood,Junying Yuan,Zahra Zakeri,Boris Zhivotovsky,Boris Zhivotovsky,Laurence Zitvogel,Gerry Melino,Gerry Melino,Guido Kroemer +186 more
TL;DR: The Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives.
Journal ArticleDOI
Synaptic Energy Use and Supply
TL;DR: This work describes how information transmission through presynaptic terminals and postsynaptic spines is related to their energy consumption, and assess which mechanisms normally ensure an adequate supply of ATP to these structures.
Journal ArticleDOI
Sugar for the brain: the role of glucose in physiological and pathological brain function
TL;DR: Recent advances in understanding how glucose metabolism sustains basic brain physiology are reviewed to form a comprehensive picture of the cooperation required between different systems and cell types, and the specific breakdowns in this cooperation that lead to disease.
Journal ArticleDOI
Mitochondrial metabolism and cancer.
Paolo E. Porporato,Nicoletta Filigheddu,José Manuel Bravo-San Pedro,Guido Kroemer,Lorenzo Galluzzi,Lorenzo Galluzzi +5 more
TL;DR: The cancer cell-intrinsic and cell-extrinsics mechanisms through which mitochondria influence all steps of oncogenesis are reviewed, with a focus on the therapeutic potential of targeting mitochondrial metabolism for cancer therapy.
Journal ArticleDOI
Mitochondria and Mitophagy: The Yin and Yang of Cell Death Control
Dieter A Kubli,Åsa B. Gustafsson +1 more
TL;DR: The importance of mitochondria and mitophagy in cardiovascular health and disease is discussed and a review of the current understanding of how these processes are regulated is provided.
References
More filters
Journal ArticleDOI
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
TL;DR: It is proposed that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass needed to produce a new cell.
Journal ArticleDOI
The Release of Cytochrome c from Mitochondria: A Primary Site for Bcl-2 Regulation of Apoptosis
TL;DR: In a cell-free apoptosis system, mitochondria spontaneously released cytochrome c, which activated DEVD-specific caspases, leading to fodrin cleavage and apoptotic nuclear morphology, and Bcl-2 acts to inhibit cy tochrome c translocation, thereby blocking caspase activation and the apoptotic process.
Journal ArticleDOI
The BCL-2 protein family: opposing activities that mediate cell death
TL;DR: New insights into interactions among BCL-2 family proteins reveal how these proteins are regulated, but a unifying hypothesis for the mechanisms they use to activate caspases remains elusive.
Journal ArticleDOI
Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death
TL;DR: It is demonstrated that Bcl-2 is an integral inner mitochondrial membrane protein of relative molecular mass 25,000 (25k) being localized to mitochondria and interfering with programmed cell death independent of promoting cell division.
Journal ArticleDOI
An inhibitor of Bcl-2 family proteins induces regression of solid tumours
Tilman Oltersdorf,Steven W. Elmore,Alexander R. Shoemaker,Robert C. Armstrong,David J. Augeri,Barbara A. Belli,Milan Bruncko,Thomas L. Deckwerth,Jürgen Dinges,Philip J. Hajduk,Mary K. Joseph,Shinichi Kitada,Stanley J. Korsmeyer,Stanley J. Korsmeyer,Kunzer Aaron R,Anthony Letai,Chi Li,Michael J. Mitten,David G. Nettesheim,Shi Chung Ng,Paul Nimmer,Jacqueline M. O'Connor,Anatol Oleksijew,Andrew M. Petros,John C. Reed,Wang Shen,Stephen K. Tahir,Craig B. Thompson,Kevin J. Tomaselli,Baole Wang,Wendt Michael D,Haichao Zhang,Stephen W. Fesik,Saul H. Rosenberg +33 more
TL;DR: Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation.