Mitochondrial adaptations to physiological vs. pathological cardiac hypertrophy

Abstract

Cardiac hypertrophy is a stereotypic response of the heart to increased workload. The nature of the workload increase may vary depending on the stimulus (repetitive, chronic, pressure, or volume overload). If the heart fully adapts to the new loading condition, the hypertrophic response is considered physiological. If the hypertrophic response is associated with the ultimate development of contractile dysfunction and heart failure, the response is considered pathological. Although divergent signalling mechanisms may lead to these distinct patterns of hypertrophy, there is some overlap. Given the close relationship between workload and energy demand, any form of cardiac hypertrophy will impact the energy generation by mitochondria, which are the key organelles for cellular ATP production. Significant changes in the expression of nuclear and mitochondrially encoded transcripts that impact mitochondrial function as well as altered mitochondrial proteome composition and mitochondrial energetics have been described in various forms of cardiac hypertrophy. Here, we review mitochondrial alterations in pathological and physiological hypertrophy. We suggest that mitochondrial adaptations to pathological and physiological hypertrophy are distinct, and we shall review potential mechanisms that might account for these differences.

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

“…62 In this study, TEM analysis showed damaged mitochondria with cristae lysis and apparent abnormal internal membrane whorls, but normal Z-bands in the heart of Gab1-cKO mice after 2 weeks of TAC or at the age of 6 months. Furthermore, Gab1-cKO mice subjected to TAC also increased mitochondrial membrane potential.…”

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.…”

“…On one hand, ROS are central for cardiac functioning under pathophysiological conditions. High levels of ROS have been found to promote the development of cardiac hypertrophy by regulating the expression of pro-hypertrophic factors [5]. 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.…”

“…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].…”

“…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]. However, the molecular mechanism of the mitochondrial alterations underlying pathological cardiac hypertrophy remains unclear.…”