Energetic Interactions Between Subcellular Organelles in Striated Muscles

Abstract

Adult striated muscle cells present highly organized structure with densely packed intracellular organelles and a very sparse cytosol accounting for only few percent of cell volume. These cells have a high and fluctuating energy demand that, in continuously working oxidative muscles, is fulfilled mainly by oxidative metabolism. ATP produced by mitochondria should be directed to the main energy consumers, ATPases of the excitation-contraction system; at the same time, ADP near ATPases should rapidly be eliminated. This is achieved by phosphotransfer kinases, the most important being creatine kinase (CK). Specific CK isoenzymes are located in mitochondria and in close proximity to ATPases, forming efficient energy shuttle between these structures. In addition to phosphotransfer kinases, ATP/ADP can be directly channeled between mitochondria co-localized with ATPases in a process called "direct adenine nucleotide channeling, DANC." This process is highly plastic so that inactivation of the CK system increases the participation of DANC to energy supply owing to the rearrangement of cell structure. The machinery for DANC is built during postnatal development in parallel with the increase in mitochondrial mass, organization, and complexification of the cell structure. Disorganization of cell architecture remodels the mitochondrial network and decreases the efficacy of DANC, showing that this process is intimately linked to cardiomyocyte structure. Accordingly, in heart failure, disorganization of the cell structure along with decrease in mitochondrial mass reduces the efficacy of DANC and together with alteration of the CK shuttle participates in energetic deficiency contributing to contractile failure.

Keywords: cardiac muscle; creatine kinase; energy metabolism; mitochondria; organelle interaction; sarcoplasmic reticulum; skeletal muscle cells.

FIGURE 1

Electron microscopic pictures of mitochondrial organization in mouse muscle cells. (A) Cardiomyocyte with regularly arranged mitochondrial rows between myofibrils. (B) Muscle fiber from white gastocnemius with small mitochondria occurring near the Z-lines. (C) Mitochondrial clusters and branching of myofibrils in CK-deficient cardiomyocyte. (D) increased mitochondrial content in CK-deficient gastrocnemius muscle. Long arrows: mitochondria; short arrows—branching of myofibrils. (E) Mitochondrial environment in 3-days old cardiomyocyte. (F) Occurrence of mitochondria in 21-days old cardiomyocyte. (G) Environment of mitochondria in control adult cardiomyocyte. (H) Mitochondrial environment in cardiomyocyte of adult failing heart. Long arrow: sarcoplasmic reticulum; ^∗cytosol; mf, myofibrils.

FIGURE 2

Intracellular adenine nucleotide transport by DANC and CK shuttle in oxidative muscle cells. ATP generated in the mitochondrial matrix by ATP synthase is transported by adenine nucleotide translocase (ANT) across the inner mitochondrial membrane to the intermembrane space whereas ADP is transported by ANT in the opposite direction. Co-localization of the mitochondria with cell ATPase (like myosin ATPase or sarcoplasmic reticulum Ca²⁺-ATPase, SERCA) allows for bi-directional direct adenine nucleotide channeling (DANC). Functional mitochondrial creatine kinase (mi-CK) coupled with ANT uses ATP and creatine to produce phosphocreatine (PCr) which diffuses in the cytosol, and ADP which is taken back in the matrix by ANT. MM-CK bound to different organelles near ATPases traps cytosolic PCr to locally rephosphorylate ADP thus replenishing local ATP concentration near ATPases. Creatine liberated by this reaction can be reused by mi-CK. Cytosolic soluble MM-CK maintains the equilibrium between all chemical actors of the CK shuttle (ATP, ADP, PCr, and creatine). Relatively high cytosolic concentrations of PCr and creatine make efficient the bi-directional flux of these two substances.