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

Abstract

Glycolysis and apoptosis are considered major but independent pathways that are critical for cell survival^{1, 2, 3, 4}. The activity of BAD, a pro-apoptotic BCL-2 family member, is regulated by phosphorylation in response to growth/survival factors^{5, 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.

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