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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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.
The authors declare that they have no competing financial interests.
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Archives of Biochemistry and Biophysics (2019)
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