Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt

Abstract

Cell survival has been closely linked to both trophic growth factor signaling and cellular metabolism. Such couplings have obvious physiologic and pathophysiologic implications, but their underlying molecular bases remain incompletely defined. As a common mediator of both the metabolic and anti-apoptotic effects of growth factors, the serine/threonine kinase Akt -also known as protein kinase B or PKB -is capable of regulating and coordinating these inter-related processes. The glucose dependence of the antiapoptotic effects of growth factors and Akt plus a strong correlation between Akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects. Mitochondrial hexokinases catalyse the first obligatory step of glucose metabolism and directly couple extramitochondrial glycolysis to intramitochondrial oxidative phosphorylation, and are thus well suited to play this role. The ability of Akt to regulate energy metabolism appears to have evolutionarily preceded the capacity to control cell survival. This suggests that Akt-dependent metabolic regulatory functions may have given rise to glucose-dependent antiapoptotic effects that evolved as an adaptive sensing system involving hexokinases and serve to ensure mitochondrial homeostasis, thereby coupling metabolism to cell survival. We hypothesize that the enlistment of Akt and hexokinase in the control of mammalian cell apoptosis evolved as a response to the recruitment of mitochondria to the apoptotic cascade. The central importance of mitochondrial hexokinases in cell survival also suggests that they may represent viable therapeutic targets in cancer.

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

“…The activity of HKs is inhibited by G-6P providing a feedback inhibition mechanism. [1][2][3][4][5] G-6P serves as a precursor for glycolysis (ATP) as well as the pentose phosphate pathway (NADPH and ribulose-5-P), glycogenesis (glycogen) and hexosamine biosynthetic pathway (UDP-GlcNAc) 2-5 ( Figure 1a). HK therefore plays important roles in the regulation of anabolic and catabolic processes.…”

“…8 HK-III is also ubiquitously expressed but not predominant in any tissue while the expression of HK-IV, glucokinase, is restricted primarily to the liver and pancreas. [2][3][4][5] Studies in the 1960s identified that significant quantities of HK-I and HK-II bind to the outer mitochondrial membrane 9,10 via a mitochondrial binding motif at the N-terminal. 11,12 HK-II binds to voltage-dependent anion channel 1 (VDAC1), the outer mitochondrial membrane protein, which interacts with the adenine nucleotide translocase (ANT), forming a contact site between the outer and inner membranes.…”

“…11,12 HK-II binds to voltage-dependent anion channel 1 (VDAC1), the outer mitochondrial membrane protein, which interacts with the adenine nucleotide translocase (ANT), forming a contact site between the outer and inner membranes. 3,4,[13][14][15][16] The mitochondrially bound HKs provide facilitation of coupling between glycolysis and oxidative phosphorylation through privileged/preferential access of HKs to ATP generated by mitochondria. The ADP generated by mitochondrial HK catalytic activity is shuttled back into mitochondria for rephosphorylation conferring metabolic advantage 4,17,18 ( Figure 1c).…”

“…HK-I has been suggested to form a tetramer preferentially at mitochondria, which becomes more resistant to product inhibition relative to the cytosolic monomeric kinase. 3,4,131,132 Although the possibility of tetramerization of HK-II has not been studied, it is notable that the region in HK-I analogous to the HK-II Thr473 region contains negative charges compared to the more positive HK-II. By adding back a negative charge to this region, Akt-mediated phosphorylation may therefore facilitate HK-II tetramer formation at mitochondria, suppressing G-6P-dependent mitoHK-II release.…”

Mfn2 is critical for brown adipose tissue thermogenic function

“…Interestingly, we also observed an increase in HKI and HKII protein levels in mitochondrial fraction of the BAT from Mfn2‐adKO mice (Fig EV5G). This is important in order to enhance glycolytic fluxes, as mitochondria‐bound HKI and HKII display increased specific activity and decreased feedback inhibition relative to their soluble monomeric counterparts in the cytosol (Robey & Hay, 2006). These changes at the protein level were in line with changes at the mRNA levels of glycolysis‐related genes, including the transcription factor HIF‐1α, a master regulator of glycolytic gene expression (Fig EV5F).…”