EN
Role of the dual leucine zipper kinase in diabetes-induced cardiomyocyte mitochondrial dysfunction (RP9)
Principial Investigators
Project Summary and Goals
Diabetes mellitus is one of the most increasing diseases worldwide and associated with several cardiovascular diseases, among them diabetic cardiomyopathy and heart failure with preserved ejection fraction (HFpEF). Appropriate mitochondrial function is crucial to supply cardiomyocytes with energy and uphold cardiac performance. Mitochondrial cAMP microdomains contribute to mitochondrial function and dynamics, and their dysregulation leads to mitophagy and apoptosis. Nicotinamide adenine dinucleotide (NAD+) is a central coenzyme in glycolysis and mitochondrial oxidative phosphorylation metabolisms and a signaling substrate for sirtuins deacetylases regulating key cellular process like metabolic gene expression or autophagy. In the hearts of db/db mice, a well-established model for type 2 diabetes with diastolic dysfunction at the age of 14-16 weeks the NAD+ levels are decreased. NAD+ is synthesised from nicotinamide mononucleotide by nicotinamide mononucleotide adenyltransferases (NMNAT) 1-3. In axons, stress-induced dual leucine zipper kinase (DLK; mitogen activated protein 3 kinase 12, MAP3K12) results in the degradation of the cytosolic NMNAT2, ultimately leading to axon degeneration. Our preliminary data show that DLK becomes activated by diabetogenic factors.
In this project, we will use our complementary expertise to follow the hypothesis that the inhibition of DLK by small molecule inhibitors or by cardiomyocyte selective deletion of Dlk will prevent diabetes-induced cardiomyocyte mitochondrial dysfunction.
Aims Addressed by the Doctoral Candidates
- Phenotypic characterization of db/db mice with cardiomyocyte selective Dlk deletion (CM-DLK-/- x db/db mice) including the analysis of mitochondrial function and dynamics.
- Study the effect of DLK on NAD+ metabolism in distinct subcellular cardiomyocyte microdomains and on the outer and inner mitochondrial membrane cAMP microdomains in isolated cardiomyocytes.
Key Techniques
- Cardiomyocytes isolation
- Förster resonance energy transfer (FRET) biosensors
- Oxygen consumption rate assay
- Confocal microscopy
- Cardiomyocyte contractility and calcium transient measurements
- Animal model of type 2 diabetes with diastolic dysfunction
Publications
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Regulation of the dual leucine zipper kinase activity through its interaction with calcineurin. Duque Escobar J, Kutschenko A, Schröder S, Blume R, Köster KA, Painer C, Lemcke T, Maison W, Oetjen E (2021). Cell Signal. 82:109953. -
Nicotinamide riboside promotes Mfn2-mediated mitochondrial fusion in diabetic hearts through the SIRT1-PGC1α-PPARα pathway. Hu l, Guo Y, Song L, Wen H, Sun N, Wang Y, Qi B, Liang Q, Geng J, Liu X, Fu F, Li Y (2022). Free Rad Bio Med. 183:75-88. -
Cardiac intermediary metabolism in heart failure: substrate use, signalling roles and therapeutic targets. Mericskay M, Zuurbier CJ, Heather LC, Karlstaedt A, Inserte J, Bertrand L, Kararigas G, Ruiz-Meana M, Maack C, Schiattarella GG (2025). Nat Rev Cardiol. Nat Rev Cardiol. 22:704-727. -
Nicotinamide riboside supplementation restores myocardial nicotinamide adenine dinucleotide levels, improves survival, and promotes protective environment post myocardial infarction. Tannous C, Ghali R, Karoui A, Habeichi NJ, Amin G, Booz GW, Mericskay M, Refaat M, Zouein FA (2024). Cardiovasc Drugs Ther. 38:1385-1396. -
Regulation of the activity of the dual leucine zipper kinase by distinct mechanisms. Köster K-A, Dethlefs M, Duque Escobar J, Oetjen E (2024). Cells 13:333.