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      Mitochondrial reticulum for cellular energy distribution in muscle

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          Abstract

          Intracellular energy distribution has attracted much interest and has been proposed to occur in skeletal muscle via metabolite-facilitated diffusion; however, genetic evidence suggests that facilitated diffusion is not critical for normal function. We hypothesized that mitochondrial structure minimizes metabolite diffusion distances in skeletal muscle. Here we demonstrate a mitochondrial reticulum providing a conductive pathway for energy distribution, in the form of the proton-motive force, throughout the mouse skeletal muscle cell. Within this reticulum, we find proteins associated with mitochondrial proton-motive force production preferentially in the cell periphery and proteins that use the proton-motive force for ATP production in the cell interior near contractile and transport ATPases. Furthermore, we show a rapid, coordinated depolarization of the membrane potential component of the proton-motive force throughout the cell in response to spatially controlled uncoupling of the cell interior. We propose that membrane potential conduction via the mitochondrial reticulum is the dominant pathway for skeletal muscle energy distribution.

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          Most cited references25

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          Transport of energy in muscle: the phosphorylcreatine shuttle.

          In order to explain the insulin-like effect of exercise, it was proposed in 1951 that contracting muscle fibers liberate creatine, which acts to produce an acceptor effect--later called respiratory control--on the muscle mitochondria. The development of this notion paralleled the controversy between biochemists and physiologists over the delivery of energy for muscle contraction. With the demonstration of functional compartmentation of creatine kinase on the mitochondrion, it became clear that the actual form of energy transport in the muscle fiber is phosphorylcreatine. The finding of an isoenzyme of creatine phosphokinase attached to the M-line region of the myofibril revealed the peripheral receptor for the mitochondrially generated phosphorylcreatine. This established a molecular basis for a phosphorylcreatine-creatine shuttle for energy transport in heart and skeletal muscle and provided an explanation for the inability to demonstrate experimentally a direct relation between muscle activity and the concentrations of adenosine triphosphate and adenosine diphosphate.
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            H2O2-induced mitochondrial fragmentation in C2C12 myocytes.

            In skeletal muscle and many other cell types, mitochondria exist as an elaborate and dynamic network in which "individual" mitochondria exist only transiently even under nonstimulated conditions. The balance of continuous mitochondrial fission and fusion defines the morphology of the mitochondrial reticulum. Environmental stimuli, such as oxidative stress, can influence fusion and fission rates, resulting in a transformation of the network's connectivity. Using confocal laser scanning microscopy of C(2)C(12) mouse myocytes, we show that acute exposure to the reactive oxygen species (ROS) hydrogen peroxide (H(2)O(2)) induces a slow fragmentation of the mitochondrial reticulum that is reversible over 24h. Although H(2)O(2) decomposes rapidly in culture medium, the full extent of fragmentation occurs 5-6h posttreatment, suggesting that H(2)O(2) affects mitochondrial morphology by modulating cellular physiology. Supraphysiological (>1 mM) concentrations of H(2)O(2) are cytotoxic, but lower concentrations (250 μM) sufficient to induce transient fragmentation do not lower cell viability. H(2)O(2)-induced mitochondrial fragmentation is preceded by decreases in inner mitochondrial membrane potential and maximal respiratory rate, suggesting a possible mechanism. Because H(2)O(2) is produced in contracting muscle, our results raise the possibility that ROS generation may contribute to exercise-induced changes in mitochondrial morphology in vivo. Copyright © 2010 Elsevier Inc. All rights reserved.
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              Is Open Access

              Acute exercise remodels mitochondrial membrane interactions in mouse skeletal muscle

              A unique property of mitochondria in mammalian cells is their ability to physically interact and undergo dynamic events of fusion/fission that remodel their morphology and possibly their function. In cultured cells, metabolic perturbations similar to those incurred during exercise influence mitochondrial fusion and fission processes, but it is unknown whether exercise acutely alters mitochondrial morphology and/or membrane interactions in vivo. To study this question, we subjected mice to a 3-h voluntarily exercise intervention following their normal physical activity patterns, and quantified mitochondrial morphology and membrane interactions in the soleus using a quantitative electron microscopy approach. A single exercise bout effectively decreased blood glucose (P < 0.05) and intramyocellular lipid content (P < 0.01), indicating increased muscle metabolic demand. The number of mitochondria spanning Z-lines and proportion of electron-dense contact sites (EDCS) between adjacent mitochondrial membranes were increased immediately after exercise among both subsarcolemmal (+116%, P < 0.05) and intermyofibrillar mitochondria (+191%, P < 0.001), indicating increased physical interactions. Mitochondrial morphology, and abundance of the mitochondrial pro-fusion proteins Mfn2 and OPA1 were unchanged. Collectively, these results support the notion that mitochondrial membrane dynamics are actively remodelled in skeletal muscle, which may be regulated by contractile activity and the metabolic state. Future studies are required to understand the implications of mitochondrial dynamics in skeletal muscle physiology during exercise and inactivity.
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                Author and article information

                Journal
                Nature
                Nature
                Springer Science and Business Media LLC
                0028-0836
                1476-4687
                July 2015
                July 29 2015
                July 2015
                : 523
                : 7562
                : 617-620
                Article
                10.1038/nature14614
                26223627
                3b8045f4-5fb4-49c0-9527-b248bf559de4
                © 2015

                http://www.springer.com/tdm

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