Mitochondrial hexokinase: cardioprotective mechanisms and its first determination in the human heart
12 / 2010 - 11 / 2012
In the past two decades the mitochondria have revealed their true nature in matters of life and death: not only are they the power houses providing the necessary ATP for the high-energy demand of the heart, they are also the cellular dictators of cell death. The glycolytic enzyme hexokinase (HK) has appeared as one of the main gatekeepers of mitochondria-induced cell death. The interaction of hexokinase with mitochondria (mitoHK) results in suppression of cell death in many cell types, and this is one of the major mechanisms why cancer cells are so difficult to kill. We have recently shown that mitochondrial hexokinase is also an important player in cell death regulation within the heart. We demonstrated that 1) HK is an integral part of cardioprotection induced by ischemic preconditioning, 2) reducing mitoHK in the heart dramatically increases ischemia-reperfusion injury (I/R), and 3) diminished mitoHK exacerbates cardiac remodelling (manuscript submitted). We are uniquely positioned to examine the role of mitochondrial hexokinase in cardiac diseases because we are the pioneers of research on the relation between mitoHK and cardioprotection, in possession of HKII+/- mice and custom made TAT-HK mitochondrial binding motif peptides, and have access to the clinic to examine for the first time a possible protective role of mitoHK in the human heart. Key objectives: 1) to resolve the underlying mechanism for protection of mitoHK against cardiac ischemia-reperfusion injury 2) to investigate the relation of mitoHK with cardioprotection in human heart.