Fueling the heartbeat: Dynamic regulation of intracellular ATP during excitation-contraction coupling in ventricular myocytes. Proc Natl Acad Sci USA 2024; 121:e2318535121. PMID: 38865270.
The human cardiac muscle requires a vast amount of adenosine triphosphate (ATP) for the approximately 100,000 beats/day. This study investigated the impact of excitation-contraction coupling on the intracellular ATP concentration ([ATP]i) in cardiac myocytes. Using mouse myocytes with a genetically encoded ATP fluorescent reporter, beat-to-beat real-time [ATP]i was recorded. The experiments revealed the following findings, some at odds with long-standing concepts. First, [ATP]i showed rapid beat-to-beat fluctuations. Diastolic [ATP]i varied between 200 and 800 µM, i.e., it was 10-fold lower than previously measured by nuclear magnetic resonance. Time-resolved measurements showed that diastolic ATP consumption by homeostatic cellular processes was significant, but the majority of ATP was used for excitation-contraction coupling. Due to the lower [ATP]i, 6 to 10% of the sarcolemmal KATP channels were open, reducing cellular Ca2+ influx and stabilizing the diastolic membrane potential. Increases in [ATP]i were closely associated with sarcoplasmic reticulum Ca2+ release and mediated by mitochondrial Ca2+ influx via the formation of mitochondrial-sarcoplasmic reticulum junctions, activating oxidative phosphorylation. Myocytes with selectively reduced mitochondrial mitofusin-2, which regulates inter-organelle Ca2+ cross talk and has been found reduced in heart failure patients, showed much smaller fluctuations of [ATP]i during excitation-contraction coupling. Activation of β-adrenergic receptors using isoproterenol lowered [ATP]i, emphasizing its heavy toll on cardiac energetics.
Take home message: These studies highlight the fluctuations of [ATP]i in cardiac myocytes during the excitation-contraction coupling, which has potential implications in myocardial health and disease.