Itaconate reduces mitochondrial respiratory threshold and improves both inotropy and lusitropy in human hypertrophic myocardium
Y Ng, Y C Koay, A Sharma, L Seth, P Bannon, S Lal, J F O'SullivanAbstract
Background
Heart failure is often associated with mitochondrial dysfunction, leading to impaired cardiac contractility and relaxation. Aconitate decarboxylase 1 (ACOD1) is a mitochondrial enzyme that plays a pivotal role in mitochondrial metabolism by regulating the synthesis of itaconate and its isomer citraconate. Both itaconate and citraconate exhibit anti-inflammatory properties and modulate immune metabolism. We have recently found that citraconate level was increased and ACOD1 was upregulated in failing hearts. However, the role of ACOD1 and its metabolites in the myocardium remains unclear.
Purpose
To determine the effects of itaconate and citraconate on mitochondrial function and contractility in physiologically relevant living human myocardial slices.
Methods
Seahorse Mito Stress test was performed in cardiomyoblasts to determine mitochondrial oxygen consumption rate. The biomechanical response of itaconate and citraconate was investigated in living human myocardial slices. Myocardial tissue samples were obtained from hypertrophic obstructive cardiomyopathy (HOCM) patients undergoing septal myectomy. The tissues were cut into ultrathin slices and cultured in biomimetic chambers with continuous electrical pacing and constant mechanical stretch, mimicking the human heart in vivo. Beating myocardial slices were treated with itaconate and citraconate to determine the biomechanical effects of these immunometabolites.
Results
Itaconate treatment suppressed maximal mitochondrial oxygen consumption rate (P<0.0001) whereas citraconate did not affect mitochondrial respiration (P=0.08) in cardiomyoblast cell line. Interestingly, itaconate treatment improved contraction as indicated by increased twitch force and maximal rate of contraction, and improved relaxation as indicated by increased maximal rate of relaxation in living human myocardial slices. Neither itaconate nor citraconate treatment affected contraction duration, time to peak and time to relaxation of the myocardial slices.
Conclusion
Itaconate may exert cardioprotective effects by damping mitochondrial respiration thresholds in addition to improving inotropy and lusitropy in failing myocardial tissue. The potential connection between these observations, whilst tantalising, requires mechanistic study.