Mitochondria in cardiac hypertrophy and heart failure

Abstract

Heart failure (HF) frequently is the unfavorable outcome of pathological heart hypertrophy. In contrast to physiological cardiac hypertrophy, which occurs in response to exercise and leads to full adaptation of contractility to the increased wall stress, pathological hypertrophy occurs in response to volume or pressure overload, ultimately leading to contractile dysfunction and HF. Because cardiac hypertrophy impairs the relationship between ATP demand and production, mitochondrial bioenergetics must keep up with the cardiac hypertrophic phenotype. We review data regarding the mitochondrial proteomic and energetic remodeling in cardiac hypertrophy, as well as the temporal and causal relationship between mitochondrial failure to match the increased energy demand and progression to cardiac decompensation. We suggest that the maladaptive effect of sustained neuroendocrine signals on mitochondria leads to bioenergetic fading which contributes to the progression from cardiac hypertrophy to failure.

Tom70 serves as a molecular switch to determine pathological cardiac hypertrophy

“…Given that Tom70 overexpression inhibited ROS generation in cardiomyocytes subjected to hypertrophic stress (Supplementary information, Figure S7), it is plausible that Tom70 may protect the heart against hypertrophic stress by targeting ROS production. On the other hand, the starvation of intracellular bioenergetics contributes to the progression of cardiac hypertrophy and heart failure [4][5][6]. In view of our finding of the beneficial effects of Tom70 on ATP production in cardiomyocytes (Supplementary information, Figure S7), Tom70 overexpression may protect the heart from hypertrophic stress by maintaining bioenergetic homeostasis.…”

“…After an initial phase of compensation, if hypertrophic growth leads to cardiac dysfunction, then the hypertrophy is considered pathological [4]. Mitochondria are central to cardiac stress responses [5,6]. Studies of pathological cardiac hypertrophy have reported obvious mitochondrial abnormalities, such as pronounced changes in the composition and function of the mitochondrial proteome [5].…”

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

“…It has been shown that PGC‐1α controls mitochondrial density50 and fatty acid oxidation51, 52 and its amount directly correlates with mitochondrial density, oxidative capacity,47 and the metabolic shift from fatty acid oxidation to glucose oxidation,51 which precedes cardiac decompensation 46. Previous studies assessing changes in the expression and activity of the ETC complexes in HF have shown variable results, and such changes may vary according to the HF model 45. Specifically, complex IV expression and COX IV activity were shown to be decreased in experimental POL‐induced systolic HF and in humans with systolic HF 53, 54.…”

Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart

“…There are many reasons why a human heart can fail, but the available evidence suggests that a functional decline of mitochondria is one of the major mechanisms underlying heart failure progression [2][3][4] . Impaired mitochondria provoke energy-generation defects, the increased production of harmful reactive oxygen species (ROS), and a greater propensity to trigger apoptosis 5 .…”