Abstract 19292: KLF4 Regulates Mitochondrial Homeostasis in the Heart
Mitochondrial homeostasis is critical for heart function and mitochondrial dysfunction contributes to numerous heart diseases such as heart failure. Our previous work indicates that mice with cardiomyocyte-restricted deficiency of KLF4 develop heart failure precipitously in response to pressure-overload but the underlying mechanisms remain unknown. We hypothesized that KLF4 may regulate mitochondrial function in the heart. Here we show that KLF4 governs mitochondrial biogenesis, metabolic function, dynamics and autophagic clearance. Adult mice with cardiac-specific KLF4 deficiency develop cardiac dysfunction with aging or in response to pressure overload characterized by reduced myocardial ATP levels, elevated ROS, and marked alterations in mitochondrial heterogeneity and alignment. Studies in mitochondria isolated from KLF4-deficient hearts revealed reduced respiration rate likely due to defects in ETC Complex I. Further, embryonic cardiac KLF4 deletion resulted in postnatal premature mortality, impaired mitochondrial biogenesis, and altered mitochondrial maturation. Mechanistically, we show that KLF4 binds to, cooperates with, and is requisite for optimal function of the ERR/PGC-1 transcriptional regulatory module on metabolic and mitochondrial targets. Finally, KLF4 also regulates autophagy through transcriptional control of a broad array of autophagy genes in cardiomyocytes. Collectively, these findings identify KLF4 as a nodal transcriptional regulator of mitochondrial homeostasis.
Author Disclosures: X. Liao: None. M. Jain: None.
- © 2015 by American Heart Association, Inc.