Probing the Role of Mitochondrial Short-chain Carbon Homeostasis in the Hypertrophied and Failing Heart

点击翻译按钮获取中文摘要

SUMMARY Current therapies for heart failure (HF) are largely directed at maladaptive extra-cardiac neurohormonal circuits in a “one size fits all” approach. There is a significant unmet need for mechanism-based therapies directly targeting the heart during early stages of HF. Increasing evidence has shown that during the development of heart failure, mitochondrial generation of ATP becomes dysregulated. A well-established metabolic signature of the failing heart is a shift from using fatty acids as the chief fuel source of the normal heart, to other fuels such as glucose. This fuel shift occurs early in the development of cardiac hypertrophy and failure. However, the potential linkage of this cardiac fuel switch to the progressive diminution in mitochondrial respiratory function and ATP producing capacity during the development of HF has not been established beyond a mere association. During the current funding period, we have made a series of discoveries that support the premise that disturbances in cardiac fatty acid oxidation (FAO) contribute to mitochondrial energetic dysfunction and the development of HF including: 1) identification of distinct “bottlenecks” in the terminal steps of the FAO pathway setting the stage for depletion of key cofactors such as Coenzyme A (CoA) and diversion of reducing equivalents away from complex I of the electron transport chain; 2) the ketone body, 3-hydroxybutryate (3OHB), an efficient cardiac fuel that bypasses long-chain FAO, reduces cardiac remodeling and ventricular dysfunction in small and large animal models of HF; and 3) increasing cardiac mitochondrial oxidative capacity, including FAO flux, by cardiac-specific deletion of the gene encoding RIP140 (Nrip1) prevents cardiac hypertrophic growth and reduces cardiac remodeling and dysfunction caused by pressure overload in mice. These findings have led to the central hypotheses of this multi-PI R01 renewal proposal: Downregulation of FAO in the hypertrophied heart results in bottlenecking within the -oxidation spiral leading to reduced capacity for mitochondrial ATP production and; reduced FAO flux sets the stage for utilization of carbon sources from glucose and other sources in anabolic pathways necessary for cardiac hypertrophic growth. These hypotheses will be tested by two aims. In Aim 1, we will conduct in-depth assessment of the cardiac functional, mitochondrial, proteomic and genomic response of wild-type, csRIP140-/- (high FAO), and csPPAR-/- (low FAO) mice during development of HF in mice. Aim 2 is designed to determine the mechanisms whereby RIP140 deficiency defends against pathological cardiac hypertrophic growth. The long-term objectives of the proposed work are to define the mechanistic events leading to mitochondrial energetic collapse in the failing heart and to identify nodal regulatory points that could serve as candidate therapeutic strategies aimed at re-balancing fuel utilization and enhancing mitochondrial ATP-producing capacity aimed at the early stages of heart failure.