The location of energetic compartments affects energetic communication in cardiomyocytes

Abstract

The heart relies on accurate regulation of mitochondrial energy supply to match energy demand. The main regulators are Ca2+ and feedback of ADP and Pi. Regulation via feedback has intrigued for decades. First, the heart exhibits a remarkable metabolic stability. Second, diffusion of ADP and other molecules is restricted specifically in heart and red muscle, where a fast feedback is needed the most. To explain the regulation by feedback, compartmentalization must be taken into account. Experiments and theoretical approaches suggest that cardiomyocyte energetic compartmentalization is elaborate with barriers obstructing diffusion in the cytosol and at the level of the mitochondrial outer membrane (MOM). A recent study suggests the barriers are organized in a lattice with dimensions in agreement with those of intracellular structures. Here, we discuss the possible location of these barriers. The more plausible scenario includes a barrier at the level of MOM. Much research has focused on how the permeability of MOM itself is regulated, and the importance of the creatine kinase system to facilitate energetic communication. We hypothesize that at least part of the diffusion restriction at the MOM level is not by MOM itself, but due to the close physical association between the sarcoplasmic reticulum (SR) and mitochondria. This will explain why animals with a disabled creatine kinase system exhibit rather mild phenotype modifications. Mitochondria are hubs of energetics, but also ROS production and signaling. The close association between SR and mitochondria may form a diffusion barrier to ADP added outside a permeabilized cardiomyocyte. But in vivo, it is the structural basis for the mitochondrial-SR coupling that is crucial for the regulation of mitochondrial Ca2+-transients to regulate energetics, and for avoiding Ca2+-overload and irreversible opening of the mitochondrial permeability transition pore.

Power Grid Protection of the Muscle Mitochondrial Reticulum

“…Conversely, the constantly active heart prioritizes energy homeostasis over mechanical power resulting in a much greater mitochondrial content. However, even with ATP producing and utilizing enzymes in such close proximity, simple diffusion of metabolites is inadequate to match ATP production and utilization in the heart (Birkedal et al, 2014). Thus, the heart requires specialized energy distribution systems to prevent potential energy gradients that could compromise steady state function.…”

Energy Metabolism in the Failing Right Ventricle: Limitations of Oxygen Delivery and the Creatine Kinase System

“…The CK system has a vital role maintaining a high [ADP] in mitochondria and a low [ADP] at the myofibrils. The less negatively charged and smaller molecular weight phosphocreatine (PCr) has greater cytosolic mobility than adenine nucleotides [58,59], so it acts as a shuttle of high energy phosphates to sites of high ATP turnover, such as the myofilaments. This also allows sudden changes in cellular energy demand to feed back to mitochondria, which sense an increase in cellular [ADP] and increase ATP production accordingly, e.g., during periods of increased heart rate.…”

Impaired ADP channeling to mitochondria and elevated reactive oxygen species in hypertensive hearts

“…Furthermore, they can be scavenged on route to sites of demand and can also act as chelators (18). The smaller, less charged, and more diffusible molecule, creatine phosphate (CrP), in conjunction with the CK shuttle theoretically decreases the reliance on adenylate diffusion (7). While the importance of the CK system seems questionable in creatine-deficient mice (30), CK enzymes appear to be essential in mammalian hearts (43).…”

“…In addition to being an "engine out of fuel," it can be characterized as an impaired motor with a faulty transmission. Typically, mitochondrial OXPHOS capacity is assessed in vitro using saturating [ADP] (1-5 mM), whereas in vivo [ADP] is low (M range) and [ATP] and [CrP] are high (mM range) (7). Bioenergetic function, in pathological states, would incorporate restricted diffusion and/or impaired facilitated transport (via the creatine shuttle).…”