Systems Level Regulation of Cardiac Energy Fluxes Via Metabolic Cycles: Role of Creatine, Phosphotransfer Pathways, and AMPK Signaling - Systems Biology of Metabolic and Signaling Networks - page 259

structural organization of cardiac cell metabolism. The T-tubular system of rat
ventricular cells creates a regular arrangement at the level of Z-line and along
myofibrils (Fig. 11.4c ) (Soeller and Cannell 1999 ). This system becomes disorga-
nized with time in cardiac cells in culture. The functional role of T-tubules was
described to provide a rapid inward spread of electrical excitation and Ca 2+ influx
that triggers Ca 2+ release from the sarcoplasmic reticulum, as well as supply of each
mitochondrion with oxygen and substrates. By using electron tomography (Hayashi
et al. 2009 ) identified anatomical couplings between opposing membranes of
T-tubules and sarcoplasmic reticulum (SR), these forming so-called Calcium
Release Units (CRU). A close localization of mitochondria and CRU favors Ca 2+
and metabolite microcompartmentation (Saks et al. 2012 ). Individual mitochondria
localize at the level of the A-band of sarcomeres and at the Z-line they are in close
contacts with jSR and the T-tubular system forming CRUs (Fig. 11.4b ). This
junctional cisterns of arrangement separates mitochondria from each other, also
making their fusion unlikely. The 3D reconstruction of the T-tubular system in
cardiac cells (Soeller and Cannell 1999 ) appears as an elaborated and effective
system of Ca 2+ , substrate, and oxygen supply from the extracellular medium. Its
discovery about a decade ago profoundly changed our knowledge of the heart cell
structure and the implications for metabolic regulation. As a matter of fact,
according to this architecture no distinction is possible between intermyofibrillar
and subsarcolemmal mitochondria, since both are in close contact with the
T-tubular system. This is in agreement with results obtained from kinetic studies
(Saks et al. 2012 ) and the fact that no electrical conduction occurs between
individual mitochondria in cardiomyocytes (Beraud et al. 2009 ; Kuznetsov
et al. 2009 ; Collins and Bootman 2003 ; Nivala et al. 2011 ; Zorov et al. 2000 ).
Simultaneous measurements of sarcomere and mitochondrial dimensions in situ
along the longitudinal axis of cardiomyocytes identified mitochondria as micron-
sized spheres localized between sarcomeres and distributed throughout the cell in a
crystal-like lattice without any visible fusion. In this organized lattice, transient
mitochondrial depolarizations (flickers), elicited by ROS-induced opening of anion
channels in the inner membrane, may propagate in cells as depolarization waves
(Nivala et al. 2011 ; Yaniv et al. 2011 ). However, electron tomographic studies
clearly revealed that there is no mitochondrial reticulum in cardiac cells; instead a
regular lattice containing 5,000-10,000 single mitochondria seems to prevail
(Nivala et al. 2011 ). In the heart, this forms the structural basis of the mitochondrial
network described by Cortassa and Aon in Chap. 5 . Taken together, all the data
described above indicate that mitochondrial respiration depends upon localized
events in their vicinity. These structurally organized functional domains—dubbed
Intracellular Energetic Units (ICEUs) (Saks 2007 ; Saks et al. 2001 , 2012 )
(Fig. 11.5 )—comprise sites of ATP hydrolysis (myofibrillar ATPases, sarcoplasmic
reticulum ATPase (SERCA), ion pumps) connected to ATP synthesis through
phosphotransfer networks. Energy transduction within ICEUs involving the Randle
and Krebs cycles of fuel supply and oxidative phosphorylation are governed by
energy-demanding reactions. Next, we analyze cardiac energy metabolism from the
perspective of regulatory interactions occurring in metabolic cycles.