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.

线粒体动力学与线粒体自噬是紧密关联的生理过程，对维持心脏稳态至关重要。本研究发现，在人类和啮齿类动物的心肌病样本中，心脏Klf9（Krüppel-like factor 9）的表达存在失调情况。年轻成年的全身性Klf9敲除小鼠与心脏特异性Klf9敲除小鼠均表现出肥厚型心肌病，且心肌细胞内出现线粒体紊乱与碎片化现象。此外，Klf9敲除的心肌细胞线粒体呼吸功能受损，心肌ATP水平降低且活性氧（Reactive Oxygen Species, ROS）水平升高。进一步研究表明，心脏Klf9缺陷会抑制线粒体自噬，进而导致功能异常线粒体积累，并在血管紧张素II（Angiotensin II, ANGII）处理后加速心力衰竭进程。与之相反，心脏特异性过表达Klf9可通过促进血管紧张素II诱导的线粒体自噬，改善心脏收缩功能。分子机制研究显示，Klf9敲除会降低过氧化物酶体增殖物激活受体γ辅激活因子1α（Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 Alpha, PGC-1α）及其参与线粒体能量代谢的靶基因的表达。此外，Klf9可直接调控线粒体融合蛋白2（Mitofusin 2, Mfn2）的表达，从而调节线粒体动力学与线粒体自噬。最后，我们发现通过腺相关病毒（Adeno-Associated Virus, AAV）介导的Mfn2基因挽救在Klf9条件性敲除（Conditional Knockout, CKO）心脏中，可改善心脏线粒体功能与收缩功能。综上，Klf9可整合心脏能量代谢、线粒体动力学与线粒体自噬过程。调控Klf9的活性或可为心力衰竭的治疗提供潜在治疗策略。