In this study we observed that 1) CypD is not necessary for HKII to bind to mitochondria in the heart, 2) deletion of the mitochondrial CypD enzyme augments hexokinase activity at the mitochondria during cardiac ischemia in the all substrates series, 3) CypD is not always mandatory for IPC protective effects, 4) glucose as sole metabolic substrate is insufficient for the Langendorff perfused mouse. Here, HK2 is linked to myocardial ischemia.