Interaction/Oligomerization of Nucleoside Diphosphate Kinase Isoforms in Pathological Processes

• Applicant: Professor Thomas Wieland, Ph.D.
• Subject Area: Pharmacology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 512541541

Nucleoside diphosphate kinases (NDPK) are enzymes that catalyze the transfer of terminal phosphate groups, mainly from adenosine triphosphate (ATP), to nucleoside diphosphates (NDP) and thus replenish nucleoside triphosphate (NTP) pools required for a wide variety of cellular processes. The class I subfamily, consisting of the isoforms NDPK A, B, C, and D, possess enzymatic activity and are known to form homo-and hetero-hexamers. Whereas NDPK D has a specific role in the mitochondrial inner membrane, the role of the other three isoforms, of which NDPK C is less abundantly expressed than NDPK A and NDPK B, is less well defined. In addition to its role in contributing to the upkeep of the cellular NTP pool, NDPK B has specific cellular functions in cell growth, differentiation, and signaling. We have previously established the essential role of NDPK B in cellular glucose metabolism, especially in the hexosamine biosynthesis pathway and protein O-GlcNAcylation. Additionally we reported that the formation of an NDPK B and NDPK C complex governs its translocation to the plasma membrane and its interaction with heterotrimeric G proteins, which contributes to the dysregulation of cardiomyocyte cAMP formation in human heart failure. As our preliminary data point to a role of NDPK B in cardiomyopathy by regulating cardiac protein O-GlcNAcylation, we hypothesize that a cooperation or interaction of NDPK B and NDPK C might be important in the development of diabetic cardiomyopathy. This proposal therefore aims (1) to elucidate the role and interaction of NDPK B and NDPK C in metabolic cardiomyopathy by using the streptozotocin-induced diabetes model in wild type and NDPK B deficient mice, (2) to investigate the interaction/oligomerization of NDPK B and NDPK C in cellular glucose metabolisms in different cardiac cell types in vitro.

• DFG Programme: Research Grants
• Co-Investigator: Privatdozentin Dr. Yuxi Feng