Disturbed cardiac mitochondrial and cytosolic calcium handling in a metabolic risk‐related rat model of heart failure with preserved ejection fraction

Abstract

Aim Calcium ions play a pivotal role in matching energy supply and demand in cardiac muscle. Mitochondrial calcium concentration is lower in animal models of heart failure with reduced ejection fraction (HFrEF), but limited information is available about mitochondrial calcium handling in heart failure with preserved ejection fraction (HFpEF). Methods We assessed mitochondrial Ca2+ handling in intact cardiomyocytes from Zucker/fatty Spontaneously hypertensive F1 hybrid (ZSF1)‐lean (control) and ZSF1‐obese rats, a metabolic risk‐related model of HFpEF. A mitochondrially targeted Ca2+ indicator (MitoCam) was expressed in cultured adult rat cardiomyocytes. Cytosolic and mitochondrial Ca2+ transients were measured at different stimulation frequencies. Mitochondrial respiration and swelling, and expression of key proteins were determined ex vivo. Results At rest, mitochondrial Ca2+ concentration in ZSF1‐obese was larger than in ZSF1‐lean. The diastolic and systolic mitochondrial Ca2+ concentrations increased with stimulation frequency, but the steady‐state levels were larger in ZSF1‐obese. The half‐widths of the contractile responses, the resting cytosolic Ca2+ concentration and the decay half‐times of the cytosolic Ca2+ transients were higher in ZSF1‐obese, likely because of a lower SERCA2a/phospholamban ratio. Mitochondrial respiration was lower, particularly with nicotinamide adenine dinucleotide (NADH) (complex I) substrates, and mitochondrial swelling was larger in ZSF1‐obese. Conclusion The free mitochondrial calcium concentration is higher in HFpEF owing to alterations in mitochondrial and cytosolic Ca2+ handling. This coupling between cytosolic and mitochondrial Ca2+ levels may compensate for myocardial ATP supply in vivo under conditions of mild mitochondrial dysfunction. However, if mitochondrial Ca2+ concentration is sustainedly increased, it might trigger mitochondrial permeability transition pore opening.

Altered mitochondrial metabolism in the insulin‐resistant heart

“…Mice with streptozotocin‐induced diabetes also exhibited reduced mitochondrial Ca 2+ , and restoration of the Ca 2+ concentration by MCU overexpression in this model resulted in increased PDC activity, a shift in metabolism towards glucose oxidation, and improved mitochondrial membrane potential and respiratory efficiency . Recently, mitochondrial Ca 2+ handling in intact cardiomyocytes from ZSF1‐obese rats, a model for diabetic cardiomyopathy, was assessed . At similar extracellular Ca 2+ and Na + concentrations, both cytosolic and mitochondrial Ca 2+ concentrations were higher in isolated cardiomyocytes from diabetic animals, because of alterations in cytosolic Ca 2+ handling and mild mitochondrial dysfunction.…”

“…At similar extracellular Ca 2+ and Na + concentrations, both cytosolic and mitochondrial Ca 2+ concentrations were higher in isolated cardiomyocytes from diabetic animals, because of alterations in cytosolic Ca 2+ handling and mild mitochondrial dysfunction. Furthermore, isolated mitochondria from these hearts were more prone to mitochondrial swelling, suggestive that the elevation in Ca 2+ concentration made these mitochondria more prone to membrane permeability pore opening and apoptosis.…”

“…Furthermore, a wide range of post‐translational modifications of mitochondrial proteins contributes to the regulation of pathways responsible for mitochondrial ROS and redox conditions, as well as for substrate metabolism, where lysine acetylation has emerged as an important modulator of cardiac metabolism. In the diabetic myocardium enhanced acetylation of mitochondrial proteins has been reported to diminish complex I function and efficiency of ATP production, as well as NADH‐linked respiration . Meanwhile, increasing evidence has highlighted how mitochondrial shape and cristae remodelling is influenced by obesity and insulin resistance, which in turn regulate mitochondrial metabolism .…”

“…In the diabetic myocardium enhanced acetylation of mitochondrial proteins has been reported to diminish complex I function and efficiency of ATP production, 120,121 as well as NADH-linked respiration. 122 Meanwhile, increasing evidence has highlighted how mitochondrial shape and cristae remodelling is influenced by obesity and insulin resistance, 123,124 which in turn regulate mitochondrial metabolism. 125 Here, we discuss the recent advances in these fields, with a particular focus on insulin resistance and T2DM.…”

Mitochondrial Calcium in heart failure with preserved ejection fraction—friend or foe?

“…In this issue of Acta Physiologica , Miranda‐Silva et al explore mitochondrial and cytosolic calcium (Ca) dynamics during excitation‐contraction coupling in a metabolic syndrome–based model of heart failure with preserved ejection fraction (HFpEF).…”