Editors' ChoiceApoptosis

Abnormal Sugar Metabolism Is Bad for the Liver

Science's STKE  26 Aug 2003:
Vol. 2003, Issue 197, pp. tw329-TW329
DOI: 10.1126/stke.2003.197.tw329

Danial et al. investigated the interaction of Bad with other mitochondrial proteins and uncovered an unexpected link between cell metabolism and cell death. The activity of Bad, a proapoptotic member of the Bcl-2 family that plays a role in activating the mitochondrial pathway to apoptosis, is regulated by its phosphorylation status. Growth or survival factor signaling leads to Bad phosphorylation and its consequent sequestration into inactive complexes (see Downward). Danial et al. used a proteomic approach to identify the components of Bad-containing protein complexes isolated from mouse liver mitochondria. Bad was associated with protein phosphatase 1 and protein kinase A catalytic subunits, WAVE-1 (a member of the Wiskott-Aldrich family of proteins that acts as an A kinase anchoring protein), and the glycolytic enzyme glucokinase. Mitochondria from Bad-deficient mice lacked the entire protein complex and showed attenuated glucokinase activity. Moreover, glucose-driven respiration in Bad–/– hepatocytes was selectively decreased. Glucose promoted Bad phosphorylation, whereas glucose deprivation led to Bad-dependent cell death. A nonphosphorylatable Bad mutant supported formation of the protein complex; glucokinase activity, however, was attenuated by this mutant. Mice that lacked Bad or expressed the nonphosphorylatable mutant showed defects in glucose homeostasis. Thus, Bad appears to have a role in regulating glucose metabolism and, conversely, may respond to abnormalities in glucose metabolism by initiating apoptosis.

N. N. Danial, C. F. Gramm, L. Scorrano, C.-Y. Zhang, S. Krauss, A. M. Ranger, S. R. Datta, M. E. Greenberg, L. J. Licklider, B. B. Lowell, S. P. Gygi, S. J. Korsmeyer, BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424, 952-956 (2003). [Online Journal]

J. Downward, Metabolism meets death. Nature 424, 896-897 (2003). [Full Text]