Sarcoplasmic reticulum-mitochondrial symbiosis: bidirectional signaling in skeletal muscle

Abstract

In mammalian skeletal muscle, an intimate association between the sarcoplasmic reticulum (SR) and mitochondria results in a symbiotic and privileged bidirectional communication between these organelles. Orthograde signaling reflects SR calcium (Ca) release stimulating mitochondrial adenosine triphosphate production via excitation-metabolism coupling. Retrograde signaling involves mitochondrial inhibition of local SR Ca release by controlling the redox environment of the Ca release unit.

Figure 1. Mitochondria are precisely localized adjacent to the calcium release unit in adult mammalian fast-twitch skeletal muscle

A. Confocal image of a single flexor digitorum brevis (FDB) skeletal muscle fiber obtained from an adult mouse (4 months of age) stained with the mitochondrial-selective dye tetramethylrhodamine ethyl ester (TMRE). TMRE fluorescence along the line of interest marked in A shows characteristic doublets of fluorescence with a sarcomeric periodicity of ~2 μm (inset). B. and C. Representative low (B) and high (C) resolution electron micrographs of FDB skeletal muscle fibers obtained from an adult mouse (4 months of age). Mitochondria (open arrows) are aligned adjacent to the triad (arrowheads), on either size of the Z-line (solid arrows). Images kindly provided by Drs. Simona Boncompagni and Feliciano Protasi.

Figure 2. Schematic representation of interactions between components of the mitochondrial calcium transport systems, the tricarboxylic acid (TCA) cycle, and the electron transport chain (ETC)

Elevations of calcium (Ca²⁺) in the mitochondrial matrix stimulate pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (ICDH), α-ketoglutarate dehydrogenase (α-KGDH), and the adenosine triphosphate (ATP) synthetic activity of the F₁F₀-ATPase (complex V). Low levels of superoxide anions (reactive oxygen species, ROS) are generated as byproducts of electrons being passed to molecular oxygen (O₂) at complex I and during the Q cycle (Q). OAA, oxaloacetate; Ac-CoA, acetyl coenzyme A; CS, citrate synthase; ACON, aconitase; α-KG, α-ketoglutarate; MDH, malate dehydrogenase; H⁺, hydrogen; I to V, complexes I to V; C, cytochrome c; ADP, adenosine diphosphate; H₂O, water; OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; Na⁺, sodium; NHE, sodium-hydrogen exchanger; NCX, sodium-calcium exchanger; CaUP, calcium uniporter; RaM; rapid mode calcium transporter; mRyR, mitochondrial ryanodine receptor.

Figure 3. Mitochondrial calcium uptake and calcium spark suppression in skeletal muscle

A. Tibialis anterior muscles expressing myoplasmic and mitochondrial calcium (Ca²⁺)-sensitive cameleons were imaged in vivo with two-photon microscopy. Time course of myoplasmic (top) and mitochondrial (bottom) Ca²⁺ transients (fluorescence, F) elicited during high frequency stimulation (0.5 s, 50 Hz stimulation train). (Reprinted from Rudolf R, Mongillo M, Magalhaes PJ, Pozzan T. In vivo monitoring of Ca²⁺ uptake into mitochondria of mouse skeletal muscle during contraction. J Cell Biol. 2004;166(4):527–36. Copyright © 2004 Rockefeller University Press. Used with permission). B. (Upper) Confocal images obtained for permeabilized extensor digitorum longus (EDL) muscle fibers perfused with L-glutamate (right), a substrate for the TCA cycle, or D-glutamate (left), which is not a substrate for the tricarboxylic acid (TCA) cycle. (Lower) Corresponding cumulative binary images for regions with F/F₀ > 3 S.D. Data reproduced with permission from J Physiol 2003;547(Pt 2):453–62 (16). C. (Upper) Confocal images obtained for a permeabilized EDL muscle fiber perfused with L-glutamate before (left) and after block of mitochondrial Ca²⁺ uptake with 20 μM Ru360 (right). (Lower) Corresponding cumulative binary images for regions with F/F₀ > 3 S.D. (Reprinted from Isaeva EV, Shirokova N. Metabolic regulation of Ca²⁺ release in permeabilized mammalian skeletal muscle fibres. J Physiol. 2003;547(Pt 2):453–62. Copyright © 2003 Blackwell Publishing. Used with permission.)

Figure 4. Bidirectional SR-mitochondrial signaling in skeletal muscle

Orthograde sarcoplasmic reticulm (SR)-mitochondrial signaling (solid lines) involves calcium (Ca²⁺) release during excitation-contraction (EC) coupling being taken up into adjacent mitochondria to stimulate oxidative phosphorylation (OXPHOS) and adenosine triphosphate (ATP) production. Retrograde mitochondrial-SR signaling (broken lines) involves the influence of mitochondrial reactive oxygen species (ROS) production and scavenging/detoxification on the local redox environment and local Ca²⁺ spark activity of the Ca²⁺ release unit (CRU). SR, sarcoplasmic reticulum; RyR1, type 1 ryanodine receptor; DHPR, dihydropyridine receptor; TT, transverse tubule; SERCA, sarco(endo)plasmic reticulum Ca²⁺-ATPase.