Project Summary
The heart is a metabolically demanding organ, and derangements in metabolic processes lead to energetic
deficits, generation of toxic metabolites, and redox imbalance, which drive pathogenesis to heart failure.
However, current therapies for heart failure do not address this fundamental issue, and there remains an unmet
clinical need for effective mechanism-based treatments. Altered transcriptional programs are thought to
contribute significantly to impaired mitochondrial oxidative phosphorylation and insufficient energy production in
heart failure. The estrogen-related receptors (ERRa, b, and g) are key regulators of mitochondrial respiration
that are downregulated in the failing heart, yet the molecular mechanisms regulating their expression and activity
remain largely unknown. In preliminary studies we have identified a novel molecular pathway that promotes the
expression of ERRb, and ERRg in cardiomyocytes, and define a new heart failure pathway linking chronic stress
to impairment of mitochondrial oxidative respiration. Our unexpected results demonstrate that the tumor
suppressor protein Neurofibromin 2 (NF2) promotes proper metabolic function, and that cardiac deletion of NF2
predisposes the heart to pathological remodeling and failure in response to LV pressure overload stress.
Transcriptome profiling of cardiac deficient NF2 cKO hearts indicated downregulation of metabolic pathways and
decreased expression/activity of ERRb and ERRg. Using a proteomics-based approach, we identified the
transcription factor Zscan21 as an interacting partner of NF2 and a novel positive regulator of metabolic gene
expression and mitochondrial oxidative respiration in cardiomyocytes. Therefore, we hypothesize that
endogenous NF2 engages the transcription factor Zscan21 to positively regulate expression of ERRb
and ERRg and promote energy production during pressure overload stress in the heart. The objectives of
the current application are to further define the clinical role of this pathway, and to elucidate the molecular
mechanisms by which NF2 regulates expression of myocardial ERRb and ERRg and prevents energy deficit.
These objectives will be accomplished in 3 aims. In Aim1, we will establish evidence of NF2 as an important and
novel mediator of cardiac metabolic coupling and energy production during the initial and late phases of pressure
overload stress. In Aim2, we will investigate in detail the molecular interaction between NF2 and Zscan21 and
determine the ability of Zscan21 to regulate expression of ERRb and ERRg, mitochondrial oxidative respiration,
and energy production in cardiomyocytes. In Aim3, we will determine the therapeutic potential of normalizing
cardiac NF2 for treatment in the pressure overload model of HFrEF. The long-term objective of this project is to
define mechanistic events that mediate mitochondrial metabolic dysfunction in heart failure and identify potential
candidates for new therapeutic strategies targeting early stages of heart failure.