Cyclophilin D ablation is associated with increased end-ischemic mitochondrial hexokinase activity

• Published in: Scientific reports 2017-10, Vol.7 (1), p.12749-13, Article 12749
• Main Authors: Nederlof, Rianne, van den Elshout, Mark A. M., Koeman, Anneke, Uthman, Laween, Koning, Iris, Eerbeek, Otto, Weber, Nina C., Hollmann, Markus W., Zuurbier, Coert J.
• Format: Article
• Language: English
• Subjects: 631/443/592/75/2/1674; 64/110; 64/60; 692/4019/592/75/2/1674; 82/80; Animals; Cyclophilins - metabolism; Female; Gene Deletion; Glucose; Glucose - pharmacology; Glutamine; Glutamine - metabolism; Heart; Hexokinase; Hexokinase - metabolism; Humanities and Social Sciences; Ischemia; Ischemic Preconditioning, Myocardial; Lactic acid; Lactic Acid - metabolism; Male; Mice, Inbred C57BL; Mitochondria; Mitochondria, Heart - metabolism; multidisciplinary; Myocardial Ischemia - metabolism; Myocardium - metabolism; Peptidyl-Prolyl Isomerase F; Perfusion; Pyruvic acid; Pyruvic Acid - metabolism; Reperfusion; Rodents; Science; Science (multidisciplinary); Substrate Specificity; Time Factors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-13096-7

Both the absence of cyclophilin D (CypD) and the presence of mitochondrial bound hexokinase II (mtHKII) protect the heart against ischemia/reperfusion (I/R) injury. It is unknown whether CypD determines the amount of mtHKII in the heart. We examined whether CypD affects mtHK in normoxic, ischemic and preconditioned isolated mouse hearts. Wild type (WT) and CypD −/− mouse hearts were perfused with glucose only and subjected to 25 min ischemia and reperfusion. At baseline, cytosolic and mtHK was similar between hearts. CypD ablation protected against I/R injury and increased ischemic preconditioning (IPC) effects, without affecting end-ischemic mtHK. When hearts were perfused with glucose, glutamine, pyruvate and lactate, the preparation was more stable and CypD ablation − resulted in more protection that was associated with increased mtHK activity, leaving little room for additional protection by IPC. In conclusion, in glucose only-perfused hearts, deletion of CypD is not associated with end-ischemic mitochondrial-HK binding. In contrast, in the physiologically more relevant multiple-substrate perfusion model, deletion of CypD is associated with an increased mtHK activity, possibly explaining the increased protection against I/R injury.