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.

Figure 1

Schematic representation of signalling pathways that may influence mitochondrial function in physiological and pathological cardiac hypertrophy. In physiological cardiac hypertrophy, as develops in response to exercise, there is increased activation of Class 1A PI3Kα, PGC-1α, and AMPK, all of which can promote mitochondrial biogenesis and increase mitochondrial oxidative capacity. Growth factors such as insulin (IR) and IGF-1R signalling might be required for the mitochondrial adaptation to exercise-induced cardiac hypertrophy. The signalling mechanisms that are activated in the compensated stage of pathological cardiac hypertrophy are relatively understudied. AMPK activation will increase glucose uptake and glycolysis. Although mitochondrial respiratory capacity remains relatively intact, FAO rates are decreased despite normal expression of PPAR-α target genes, suggesting allosteric regulatory mechanisms. There is scant published evidence to support any increase in mitochondrial biogenesis at this stage. Most studies have focused on the models in which LV dysfunction is present (decompensated). In this stage, there are perturbations in many signalling pathways that conspire to impair mitochondrial function. These include decreased expression or activity of transcriptional regulators that govern mitochondrial biogenesis and oxidative capacity (i.e. PGC-1α, ERRα, and PPAR-α) and decreased transcription of mitochondrial DNA. Increased G-protein-coupled receptor signalling activates Class1B PI3Kγ that leads to constitutive activation of Akt, which may repress mitochondrial function. Activation of HIF-1α leads to a PPAR-α-mediated increase in FA uptake and lipogenesis that may promote lipotoxicity, which could further impair mitochondrial function. Reduced cardiolipin content and remodelling of the mitochondrial proteome also contribute to mitochondrial dysfunction. Mitochondrial dysfunction promotes oxidative stress that leads to a vicious cycle of progressive mitochondrial damage.