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

Nika N. Danial, Colette F. Gramm, Luca Scorrano, Chen-Yu Zhang, Stefan Krauss, Ann M. Ranger, Sandeep Robert Datta, Michael E. Greenberg, Lawrence J. Licklider, Bradford B. Lowell, Steven P. Gygi and Stanley J. Korsmeyer ()
Additional contact information
Nika N. Danial: Harvard Medical School
Colette F. Gramm: Harvard Medical School
Luca Scorrano: Harvard Medical School
Chen-Yu Zhang: Harvard Medical School
Stefan Krauss: Harvard Medical School
Ann M. Ranger: Harvard Medical School
Sandeep Robert Datta: Harvard Medical School
Michael E. Greenberg: Harvard Medical School
Lawrence J. Licklider: Harvard Medical School
Bradford B. Lowell: Harvard Medical School
Steven P. Gygi: Harvard Medical School
Stanley J. Korsmeyer: Harvard Medical School

Nature, 2003, vol. 424, issue 6951, 952-956

Abstract: 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.

Date: 2003
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DOI: 10.1038/nature01825

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