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Letters to Nature

Nature 424, 952-956 (21 August 2003) | doi:10.1038/nature01825; Received 20 March 2003; Accepted 27 May 2003

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

Nika N. Danial1, Colette F. Gramm1, Luca Scorrano1,5, Chen-Yu Zhang2, Stefan Krauss2, Ann M. Ranger1, Sandeep Robert Datta3, Michael E. Greenberg3, Lawrence J. Licklider4, Bradford B. Lowell2, Steven P. Gygi4 & Stanley J. Korsmeyer1

  1. Howard Hughes Medical Institute, Dana-Faber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
  2. Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
  3. Division of Neuroscience, Children's Hospital, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA
  4. Department of Cell Biology, Taplin Biological Mass Spectrometry Facility, Harvard Medical School, Boston, Massachusetts 02115, USA
  5. Present address: Venetian Institute of Molecular Medicine, Padova 35129, Italy

Correspondence to: Stanley J. Korsmeyer1 Email: stanley_korsmeyer@dfci.harvard.edu

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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.