Klf9 is essential for cardiac mitochondrial homeostasis

Mitochondrial dynamics and mitophagy are intimately linked physiological processes that are essential for cardiac homeostasis. Here we show that cardiac Klf9 is dysregulated in human and rodent cardiomyopathy. Young adult global and cardiac-specific Klf9-deficient mice displayed hypertrophic cardiomyopathy, and exhibited mitochondrial disarray and fragmentation in cardiomyocytes. Besides, mitochondrial respiratory function was impaired in Klf9-knockout cardiomyocytes, with reduced myocardial ATP levels and elevated ROS. Furthermore, cardiac Klf9 deficiency inhibited mitophagy, thereby leading to accumulation of dysfunctional mitochondria and acceleration of heart failure in response to angiotensin II (ANGII) treatment. In contrast, cardiac-specific Klf9 transgene improved cardiac systolic function via promoting mitophagy in response to ANGII treatment. Molecular mechanism studies indicated that Klf9 knockout decreased the expression of PGC-1α and its target genes involved in mitochondrial energy metabolism. Moreover, Klf9 directly controlled the expression of Mfn2, thereby regulating mitochondrial dynamics and mitophagy. Finally, we found that AAV-mediated Mfn2 rescue in Klf9-CKO heart 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.