Abstract Body: Background: Mitochondrial dysfunction constitutes an important aspect of heart failure etiopathogenesis and progression. However, the molecular mechanisms are still largely unknown. The transcription factor, Foxm1 plays an essential role in cardiovascular development. However, a role for Foxm1 in postmitotic cardiomyocytes (CMs) remains incompletely understood.
Methods and Results: We found that Foxm1 expression was clearly upregulated in failing human myocardium. Adult mice with CM-specific loss of Foxm1 presented with a dilated cardiomyopathy associated with mitochondrial dysfunction. Transcriptomic and proteomic profiling of Foxm1 deficiency mice revealed robust and relatively specific downregulation of gene programs important for mitochondrial energetics and homeostasis. By analysis of proteome and ubiquitinome data, we demonstrated that Foxm1 deletion in CMs causes greater LKB1 ubiquitination and impairing AMPK signaling pathway and energy metabolism. Interatomic analysis identified E3 ligase-MKRN1 as a key partner of LKB1 and MKRN1 served as a specific regulator of LKB1-mediated AMPK signaling pathway through direct conjugation of K48-linked ubiquitin chains to LKB1 on positions Lys146. We provided evidence that genetic knockout of MKRN1 in CM effectively rescued cardiac dysfunction and pathology associated with Foxm1 deficiency in vivo, revealing a Foxm1-mediated, MKRN1-dependent energy-sensitive LKB1-AMPK signaling pathway in regulating myocardial homeostasis and remodeling. In striking contrast to Foxm1 knockout, genetic overexpression of Foxm1 protected mouse and pig hearts from reperfusion injury and remodeling.
Conclusions: Taken together, the findings of this study provide new insights into the previously unrecognized role of Foxm1 in mitochondrial bioenergetics and the progression of heart failure. Consequently, these findings may provide new therapeutic options for patients with heart failure.