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

Abstract

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.

Sugar-free approaches to cancer cell killing

“…Baddeficient murine hepatocytes deprived of glucose are strikingly protected from cell death compared with their normal counterparts (Danial et al, 2003). These results suggest that Bad functions as a proapoptotic BH3-only protein in response to glucose deprivation.…”

“…Its phosphorylation by growth factor-activated kinases triggers its binding to 14-3-3 proteins, thus inhibiting its interaction with Bcl-2 antiapoptotic proteins and impeding its proapoptotic functions (Zha et al, 1996). It was shown by Danial et al (2003) that phosphorylation of the BH3 domain of Bad promotes hexokinase IV activity. On the other hand, glucose deprivation promotes dephosphorylation of the BH3 motive, correlating with apoptosis induction.…”

“…On the other hand, glucose deprivation promotes dephosphorylation of the BH3 motive, correlating with apoptosis induction. Furthermore, treatment of human leukemic cells with a glycolytic inhibitor (3-BrPA) led to Bad dephosphorylation and Bax oligomerization on mitochondria (Danial et al, 2003;Xu et al, 2005). Thus, the phosphorylation status of Bad seems to have opposite effects on its two main functions: phosphorylation promotes glycolysis while inhibiting apoptosis.…”

BCL-2 in the crosshairs: tipping the balance of life and death

“…12 58 Alternatively, select BH3-only proteins such as BID and BIM may also trigger BAX/BAK directly, 22,[58][59][60][61][62] and are therefore termed 'activators'. 57 In addition to these internal familybased interactions, BCL-2 proteins associate with a host of other cellular proteins 31,47,[63][64][65][66][67][68][69][70][71] and have emerging roles in diverse physiologic pathways including glucose metabolism 20 and the DNA-damage response. 24,40 …”

Alternate functions of viral regulators of cell death

“…For example, cellular antiapoptotic Bcl-2 homologs are implicated in regulating autophagy, calcium homeostasis and cellular bioenergetics. [24][25][26][27][28] Thus, viral Bcl-2 homologs likely also engage in these processes, although their biochemical mechanisms remain largely unknown.…”