title: The dynamic regulation of myocardial oxidative phosphorylation: analysis of the response time of oxygen consumption.
abstract: Although usually steady-state fluxes and metabolite levels are assessed for the study of metabolic regulation, much can be learned from studying the transient response during quick changes of an input to the system. To this end we study the transient response of O2 consumption in the heart during steps in heart rate. The time course is characterized by the mean response time of O2 consumption which is the first statistical moment of the impulse response function of the system (for mono-exponential responses equal to the time constant). The time course of O2 uptake during quick changes is measured with O2 electrodes in the arterial perfusate and venous effluent of the heart, but the venous signal is delayed with respect to O2 consumption in the mitochondria due to O2 diffusion and vascular transport. We correct for this transport delay by using the mass balance of O2, with all terms (e.g. O2 consumption and vascular O2 transport) taken as function of time. Integration of this mass balance over the duration of the response yields a relation between the mean transit time for O2 and changes in cardiac O2 content. Experimental data on the response times of venous [O2] during step changes in arterial [O2] or in perfusion flow are used to calculate the transport time between mitochondria and the venous O2 electrode. By subtracting the transport time from the response time measured in the venous outflow the mean response time of mitochondrial O2 consumption (tmito) to the step in heart rate is obtained. In isolated rabbit heart we found that tmito to heart rate steps is 4-12 s at 37 degrees C. This means that oxidative phosphorylation responds to changing ATP hydrolysis with some delay, so that the phosphocreatine levels in the heart must be decreased, at least in the early stages after an increase in cardiac ATP hydrolysis. Changes in ADP and inorganic phosphate (Pi) thus play a role in regulating the dynamic adaptation of oxidative phosphorylation, although most steady state NMR measurements in the heart had suggested that ADP and Pi do not change. Indeed, we found with 31P-NMR spectroscopy that phosphocreatine (PCr) and Pi change in the first seconds after a quick change in ATP hydrolysis, but remarkably they do this significantly faster (time constant approximately 2.5 s) than mitochondrial O2 consumption (time constant 12 s). Although it is quite likely that other factors besides ADP and Pi regulate cardiac oxidative phosphorylation, a fascinating alternative explanation is that the first changes in PCr measured with NMR spectroscopy took exclusively place in or near the myofibrils, and that a metabolic wave must then travel with some delay to the mitochondria to stimulate oxidative phosphorylation. The tmito slows with falling temperature, intracellular acidosis, and sometimes also during reperfusion following ischemia and with decreased mitochondrial aerobic capacity. In conclusion, the study of the dynamic adaptation of cardiac oxidative phosphorylation to demand using the mean response time of cardiac mitochondrial O2 consumption is a very valuable tool to investigate the regulation of cardiac mitochondrial energy metabolism in health and disease.
authors.affiliation: Laboratory for Physiology, Institute for Cardiovascular Research (ICaR-VU), Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: van Beek
authors.forename: X
authors.initials: X
authors.lastname: Tian
authors.forename: C J
authors.initials: CJ
authors.lastname: Zuurbier
authors.forename: B
authors.initials: B
authors.lastname: de Groot
authors.forename: C J
authors.initials: CJ
authors.lastname: van Echteld
authors.forename: M H
authors.initials: MH
authors.lastname: Eijgelshoven
authors.forename: J B
authors.initials: JB
authors.lastname: Hak
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism / Q000502:physiology; D006321:Heart / Q000502:physiology*; D006331:Heart Diseases / Q000503:physiopathology; D006339:Heart Rate / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D008928:Mitochondria / Q000378:metabolism*; D009210:Myofibrils / Q000502:physiology; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000502:physiology*; D010725:Phosphocreatine / Q000378:metabolism; D011817:Rabbits; D013696:Temperature
chemical_list: D010725:Phosphocreatine; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate