HK2/hexokinase-II integrates glycolysis and autophagy to confer cellular protection

Abstract

Hexokinases (HKs) catalyze the first step of glucose metabolism, phosphorylating glucose to glucose 6-phosphate (G6P). HK2/hexokinase-II is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues and is also upregulated in many types of tumors associated with enhanced aerobic glycolysis (the Warburg effect). Accumulating evidence indicates that HK2 plays an important role not only in glycolysis but also in cell survival. Although there is increasing recognition that cellular metabolism and cell survival are closely related, the molecular link between metabolism and autophagic pathways has not been fully elucidated. We recently discovered that HK2 facilitates autophagy in response to glucose deprivation (HK substrate deprivation) to protect cardiomyocytes, and suggest that HK2 functions as a molecular switch from glycolysis to autophagy to ensure cellular energy homeostasis under starvation conditions.

Keywords: MTORC1; autophagy; glucose 6-phosphate; glycolysis; hexokinase-II.

Figure 1.

HK2 detects glucose depletion to bind and inhibit MTORC1, enhancing autophagy. In the presence of glucose, the binding is inhibited by glucose 6-phosphate (G6P) generated by HK2 catalytic activity. Glc, glucose.