BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis.
Glycolysis and apoptosis are considered major but independent pathways that are critical for cell survival. The activity of BAD, a pro-apoptotic BCL-2 family member, is regulated by phosphorylation in response to growth/survival factors. 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 A and protein phosphatase 1 (PP1) catalytic units, Wiskott-Aldrich family member WAVE-1 as an A kinase anchoring protein, and glucokinase (hexokinase IV). 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) mutant 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.
Danial
Nika N
NN
Howard Hughes Medical Institute, Dana-Faber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Gramm
Colette F
CF
Scorrano
Luca
L
Zhang
Chen-Yu
CY
Krauss
Stefan
S
Ranger
Ann M
AM
Datta
Sandeep Robert
SR
Greenberg
Michael E
ME
Licklider
Lawrence J
LJ
Lowell
Bradford B
BB
Gygi
Steven P
SP
Korsmeyer
Stanley J
SJ
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D020035:Holoenzymes / Q000378:metabolism; D006706:Homeostasis; D046911:Macromolecular Substances; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000737:chemistry* / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D040901:Proteomics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051025:bcl-Associated Death Protein
C494820:Bad protein, mouse; D002352:Carrier Proteins; D020035:Holoenzymes; D046911:Macromolecular Substances; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; D005941:Glucokinase; D005947:Glucose