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BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis

Nature volume 424, pages 952–956 (2003)Cite this article

Abstract

Glycolysis and apoptosis are considered major but independent pathways that are critical for cell survival1,2,3,4. The activity of BAD, a pro-apoptotic BCL-2 family member, is regulated by phosphorylation in response to growth/survival factors5,6,7,8. Here we undertook a proteomic analysis to assess whether BAD might also participate in mitochondrial physiology. In liver mitochondria, BAD resides in a functional holoenzyme complex together with protein kinase A7 and protein phosphatase 1 (PP1) catalytic units9, Wiskott–Aldrich family member WAVE-1 as an A kinase anchoring protein10, and glucokinase (hexokinase IV)11. BAD is required to assemble the complex in that Bad-deficient hepatocytes lack this complex, resulting in diminished mitochondria-based glucokinase activity and blunted mitochondrial respiration in response to glucose. Glucose deprivation results in dephosphorylation of BAD, and BAD-dependent cell death. Moreover, the phosphorylation status of BAD helps regulate glucokinase activity. Mice deficient for BAD or bearing a non-phosphorylatable BAD(3SA) mutant12 display abnormal glucose homeostasis including profound defects in glucose tolerance. This combination of proteomics, genetics and physiology indicates an unanticipated role for BAD in integrating pathways of glucose metabolism and apoptosis.

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Figure 1: Characterization of mitochondrial complexes containing BAD.
Figure 2: Components of a mitochondrial BAD complex.
Figure 3: Aberrations in glucokinase activity, glucose homeostasis and glucose-withdrawal-induced cell death in Bad-/- mice.
Figure 4: Requirement of BAD phosphorylation in the regulation of mitochondrial glucokinase activity and glucose homeostasis.

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Acknowledgements

We thank M. Ryan, G. Shore, J. Scott, M. Magnuson and B. Spiegelman for reagents; M. Ryan and J. Opferman for technical advice; B. Kahn and O. Peroni for discussion; S. Wade, J. Fisher and J. Sturgill for animal care; U. Maduekwe for technical assistance; and E. Smith for manuscript preparation. N.N.D. is a recipient of the Cancer Research Fund of Damon Runyon Foundation fellowship. This work is supported in part by a NIH grant.

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Author notes

  1. Luca Scorrano

    Present address: Venetian Institute of Molecular Medicine, Padova, 35129, Italy

Authors and Affiliations

  1. Howard Hughes Medical Institute, Dana-Faber Cancer Institute, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Nika N. Danial, Colette F. Gramm, Luca Scorrano, Ann M. Ranger & Stanley J. Korsmeyer

  2. Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, 02215, USA

    Chen-Yu Zhang, Stefan Krauss & Bradford B. Lowell

  3. Division of Neuroscience, Children's Hospital, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Sandeep Robert Datta & Michael E. Greenberg

  4. Department of Cell Biology, Taplin Biological Mass Spectrometry Facility, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Lawrence J. Licklider & Steven P. Gygi

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Correspondence to Stanley J. Korsmeyer.

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Danial, N., Gramm, C., Scorrano, L. et al. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424, 952–956 (2003). https://doi.org/10.1038/nature01825

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