Hexokinase: A Glycolytic Enzyme with an Inflammatory Ischemia and Reperfusion Connection

Hydroxyl radicals are known to promote inflammation (1, 2). One way that hydroxyl radicals can increase is due to ischemia-reperfusion (I/R) injury. Ultimately I/R injury affects the mitochondrial membrane and the apoptotic processes that normally occur. The mitochondria play a key role in the fate of the cell, determining whether or not the cell undergoes apoptosis. When there is an increase in hydroxyl radicals the lipids in the mitochondrial membrane begin to react with the hydroxyl radicals resulting in the mitochondrial membrane becoming leaky. A leaky mitochondrial membrane allows calcium that is normally kept at low concentrations in the mitochondria to be dramatically increased, wreaking havoc on the cell calcium homeostasis. The precise signaling pathways involved in calcium regulation that ultimately affect cell death are not well understood (3). Cell death is a serious consequence, thus there are many factors that affect cell death, including Akt, Bax, and Bcl2. Akt inhibits cell death and has a significant role in cell survival and tumor formation (4, 5). A glycolytic enzyme, hexokinase that has been overlooked in the past has recently been given some attention due to its interaction with Akt. How Akt, hexokinase and hydroxyl radicals interact to affect cell survival or cell death is currently unknown and is the reason for this editorial. As new advances are incorporated into the basic sciences of glycolysis and Akt and the clinical sciences of ischemia and reperfusion injury, translational efforts will be more frequently considered and applied. It is our ultimate goal to encourage investigators to utilize concepts presented here to move forward in the field of ischemia and reperfusion.

I/R injury results in an increase in inflammation through many cytokines, including TNF-α. Inflammation has been shown to increase a person's cancer risk (6). The relationship between TNF-α and Akt continues to be defined, however Yang et al. have shown a relationship between Akt and TNF-α in hepatocellular carcinogenesis (7). Additionally, a relationship has been established between hexokinase and Akt (8). There are four hexokinase isoforms; hexokinase I and II are both considered mitochondrial hexokinases because they can bind to the mitochondrial membrane (9). The relationship between hexokinase and Akt is currently being investigated to better understand which isoform of hexokinase is involved in cell survival. Due to the mitochondrial role as a gatekeeper of apoptosis, the ability of hexokinase II to bind to the mitochondrial membrane has serious implications on apoptosis and cell survival (10).

Akt has been established as a pro-survival signaling protein (11) that regulates signaling upstream of hexokinase (12). With the discovery of hexokinase II as a pro-survival enzyme new research is currently underway to explore the role of hexokinase II in cancer (13-15). Thus, hexokinase is an enzyme with other important functions beyond being the first enzyme in the glycolytic pathway. As such, hexokinases are beginning to be categorized as inflammatory regulatory proteins (16). Defining the interaction of hexokinase with inflammatory proteins such as TNF-alpha will ultimately help our understanding of the process of host cell death. We believe, that the establishment of these relationships will help to further define the mechanisms behind I/R injury, cancer and other inflammatory disease processes.