| First Author | Zhang L | Year | 2024 |
| Journal | Nat Cardiovasc Res | Volume | 3 |
| Issue | 11 | Pages | 1318-1336 |
| PubMed ID | 39528719 | Mgi Jnum | J:358599 |
| Mgi Id | MGI:7782866 | Doi | 10.1038/s44161-024-00561-6 |
| Citation | Zhang L, et al. (2024) Klf9 is essential for cardiac mitochondrial homeostasis. Nat Cardiovasc Res 3(11):1318-1336 |
| abstractText | Mitochondrial dynamics and mitophagy are intimately linked physiological processes that are essential for cardiac homeostasis. Here we show that cardiac Kruppel-like factor 9 (Klf9) is dysregulated in human and rodent cardiomyopathy. Both global and cardiac-specific Klf9-deficient mice displayed hypertrophic cardiomyopathy. Klf9 knockout led to mitochondrial disarray and fragmentation, impairing mitochondrial respiratory function in cardiomyocytes. Furthermore, cardiac Klf9 deficiency inhibited mitophagy, thereby causing accumulation of dysfunctional mitochondria and acceleration of heart failure in response to angiotensin II treatment. In contrast, cardiac-specific Klf9 transgene improved cardiac systolic function. Mechanistically, Klf9 knockout decreased the expression of PGC-1alpha and its target genes involved in mitochondrial energy metabolism. Moreover, Klf9 controlled the expression of Mfn2, thereby regulating mitochondrial dynamics and mitophagy. Finally, adeno-associated virus-mediated Mfn2 rescue in Klf9-CKO hearts improved cardiac mitochondrial and systolic function. Thus, Klf9 integrates cardiac energy metabolism, mitochondrial dynamics and mitophagy. Modulating Klf9 activity may have therapeutic potential in the treatment of heart failure. |
