Transfer and Tunneling of Ca2+ from Sarcoplasmic Reticulum to Mitochondria in Skeletal Muscle

Shkryl, Vyacheslav M.; Shirokova, Natalia

doi:10.1074/jbc.m505024200

Cited by 88 publications

(75 citation statements)

References 29 publications

(19 reference statements)

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“…Although Ca 2ϩ uptake by individual mitochondria is limited, aggregate Ca 2ϩ uptake by a sufficiently large number of strategically located mitochondria significantly blunts local and global cytoplasm Ca 2ϩ transients under physiological conditions (Rudolf et al, 2004). Similar results were found in single extensor digitorum longus (EDL) and soleus fibers (Shkryl and Shirokova, 2006). Moreover, contractile relaxation is accelerated in mitochondrial-rich skeletal muscle fibers, but not in more glycolytic fibers with fewer active and respiring mitochondria (Gillis, 1997).…”

Section: Introductionsupporting

confidence: 63%

“…As mitochondrial Ca 2ϩ uptake during transient elevations in cytoplasmic Ca 2ϩ requires communication through spatially confined, local signaling microdomains, the intimate mitochondrion-CRU assembly described here provides the structural framework required for local mitochondrial Ca 2ϩ uptake observed during SR Ca 2ϩ release in adult skeletal muscle (Gillis, 1997;Rizzuto et al, 1998;Shkryl and Shirokova, 2006). We found that tethers bridge SR to mitochondria on the side opposite to the location of RyRfeet.…”

Section: Discussionmentioning

confidence: 81%

“…Unlike other cell types in which mitochondria are dynamic organelles that exhibit a significant degree of motility within the cytoplasm (Bereiter-Hahn and Voth, 1994), triad-targeted mitochondria in adult skeletal muscle are remarkably stable and immotile (see Supplemental Movies S3 and S4). Because CRU-mitochondrion Ca 2ϩ cross-talk in skeletal muscle operates via local signaling microdomains (Shkryl and Shirokova, 2006), this "privileged" signaling could best be ensured by restricting mitochondria to a location immediately adjacent to sites of Ca 2ϩ release by a strong structural anchoring mechanism.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondria Are Linked to Calcium Stores in Striated Muscle by Developmentally Regulated Tethering Structures

Boncompagni¹,

Rossi

Micaroni

et al. 2009

MBoC

245

272

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Bi-directional calcium (Ca 2؉ ) signaling between mitochondria and intracellular stores (endoplasmic/sarcoplasmic reticulum) underlies important cellular functions, including oxidative ATP production. In striated muscle, this coupling is achieved by mitochondria being located adjacent to Ca 2؉ stores (sarcoplasmic reticulum [SR]) and in proximity of release sites (Ca 2؉ release units [CRUs]). However, limited information is available with regard to the mechanisms of mitochondrial-SR coupling. Using electron microscopy and electron tomography, we identified small bridges, or tethers, that link the outer mitochondrial membrane to the intracellular Ca 2؉ stores of muscle. This association is sufficiently strong that treatment with hypotonic solution results in stretching of the SR membrane in correspondence of tethers. We also show that the association of mitochondria to the SR is 1) developmentally regulated, 2) involves a progressive shift from a longitudinal clustering at birth to a specific CRU-coupled transversal orientation in adult, and 3) results in a change in the mitochondrial polarization state, as shown by confocal imaging after JC1 staining. Our results suggest that tethers 1) establish and maintain SR-mitochondrial association during postnatal maturation and in adult muscle and 2) likely provide a structural framework for bi-directional signaling between the two organelles in striated muscle.

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Section: Introductionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondria Are Linked to Calcium Stores in Striated Muscle by Developmentally Regulated Tethering Structures

Boncompagni¹,

Rossi

Micaroni

et al. 2009

MBoC

245

272

View full text Add to dashboard Cite

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“…We have recently demonstrated that the local Ca 2ϩ coupling is regulated by the spacing between the ER and outer mitochondrial membrane and that the ER-mitochondrial interface is secured by protein tethers (8). Local [Ca 2ϩ ] regulation has also been shown to support the Ca 2ϩ signal propagation from the ryanodine receptors (RyR, the phylogenetic ancestors of the inositol 1,4,5-trisphosphate receptor) to the mitochondria in cardiac muscle cells (9,10) and in skeletal muscle (11)(12)(13). However, whether the local Ca 2ϩ communication between the SR and mitochondria is supported by physical coupling is yet to be elucidated.…”

Section: Activation Of Camentioning

confidence: 99%

Physical Coupling Supports the Local Ca2+ Transfer between Sarcoplasmic Reticulum Subdomains and the Mitochondria in Heart Muscle

Garcı́a-Pérez

Hajnóczky

Csordás

2008

Journal of Biological Chemistry

133

112

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In many cell types, transfer of Ca 2؉ released via ryanodine receptors (RyR) to the mitochondrial matrix is locally supported by high [Ca 2؉ ] microdomains at close contacts between the sarcoplasmic reticulum (SR) and mitochondria. Here we studied whether the close contacts were secured via direct physical coupling in cardiac muscle using isolated rat heart mitochondria (RHMs). "Immuno-organelle chemistry" revealed RyR2 and calsequestrin-positive SR particles associated with mitochondria in both crude and Percoll-purified "heavy" mitochondrial fractions (cRHM and pRHM), to a smaller extent in the latter one. Mitochondria-associated vesicles were also visualized by electron microscopy in the RHMs. Western blot analysis detected greatly reduced presence of SR markers (calsequestrin, SERCA2a, and phospholamban) in pRHM, suggesting that the mitochondria-associated particles represented a small subfraction of the SR. signal propagation from the ryanodine receptors (RyR, the phylogenetic ancestors of the inositol 1,4,5-trisphosphate receptor) to the mitochondria in cardiac muscle cells (9, 10) and in skeletal muscle (11-13). However, whether the local Ca 2ϩ communication between the SR and mitochondria is supported by physical coupling is yet to be elucidated. Very recently, Protasi and co-workers (14, 15) have visualized tethering structures between SR and mitochondria in electron micrographs and tomographs of skeletal muscle, although those data did not examine the involvement of the tethers in the Ca 2ϩ communication between the organelles. A local metabolic triangle between the sarcomere, SR, and mitochondria that could be dissociated by limited proteolysis in permeabilized cardiomyocytes has also been described earlier (16). Here, we studied the preservation of the SR-mitochondrial associations and local Ca 2ϩ coupling between RyR and mitochondria by visualization of individual organelles and monitoring their function in mitochondria isolated from rat heart homogenates. MATERIALS AND METHODS Chemicals/ImmunochemicalsFluorescent probes and fluorescently labeled secondary antibodies were from Molecular Probes (Eugene, OR), except the Ca 2ϩ probes fura2 (K ϩ salt) and rhod2 acetoxymethylester (rhod2/AM), which were purchased from Teflabs (Austin, TX). Primary antibodies were obtained as follows: mouse monoclonal: anti-RyR2 from ABR (MA3-916), anti-phospholamban from Abcam (ab2865), and anti-cytochrome oxidase subunit 1 from Molecular Probes (A6403); rabbit polyclonal: anti-RyR2 * This work was supported by an American Heart Association Grant SDG 0435236N. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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“…1C (numbers of cells and events averaged are given in the Table 1). Fig 1D is [Ca 2ϩ ] increases in mitochondria upon Ca 2ϩ release (12) and mag-indo-1 loads in mitochondria as well as SR (11). When imaging in cells exposed to four inhibitors of mitochondrial Ca 2ϩ uptake ( Fig.…”

Section: Simultaneousmentioning

confidence: 99%

Depletion “skraps” and dynamic buffering inside the cellular calcium store

Launikonis

Zhou²,

Royer³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

154

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Ca 2؉ signals, produced by Ca 2؉ release from cellular stores, switch metabolic responses inside cells. In muscle, Ca 2؉ sparks locally exhibit the rapid start and termination of the cell-wide signal. By imaging Ca 2؉ inside the store using shifted excitation and emission ratioing of fluorescence, a surprising observation was made: Depletion during sparks or voltage-induced cell-wide release occurs too late, continuing to progress even after the Ca 2؉ release channels have closed. This finding indicates that Ca 2؉ is released from a ''proximate'' compartment functionally in between store lumen and cytosol. The presence of a proximate compartment also explains a paradoxical surge in intrastore Ca 2؉ , which was recorded upon stimulation of prolonged, cell-wide Ca 2؉ release. An intrastore surge upon induction of Ca 2؉ release was first reported in subcellular store fractions, where its source was traced to the store buffer, calsequestrin. The present results update the evolving concept, largely due to N. Ikemoto and C. Kang, of calsequestrin as a dynamic store. Given the strategic location and reduction of dimensionality of Ca 2؉ -adsorbing linear polymers of calsequestrin, they could deliver Ca 2؉ to the open release channels more efficiently than the luminal store solution, thus constituting the proximate compartment. When store depletion becomes widespread, the polymers would collapse to increase store [Ca 2؉ ] and sustain the concentration gradient that drives release flux.calcium signaling ͉ calcium sparks ͉ excitation-contraction coupling ͉ sarcoplasmic reticulum ͉ skeletal muscle R apid changes in intracellular cytosolic [Ca 2ϩ ] are required for signaling functions in many cell types (1). These changes are achieved via Ca 2ϩ release through channels, ryanodine receptors (RyRs), which must open and close quickly. To increase its speed, gating of RyRs relies on effects of the permeant ion, including channel opening by elevated cytosolic [Ca 2ϩ ] (2). In muscle, the desirable fast kinetic features are already present in its elementary signaling events, Ca 2ϩ sparks (3), which involve the nearly simultaneous opening (4) of a number of channels (5), followed by their synchronized closing (4). Thus, this gating does not follow the usual Markovian rules for channels that evolve independently but requires timekeeping and synchronization (6). In cardiac muscle, depletion of sarcoplasmic reticulum (SR) Ca 2ϩ is the likely timer of channel closing, and the substantial depletion that follows the cardiac beat (7) was imaged as ''blinks'' associated with Ca 2ϩ sparks (8). The sensor that translates depletion into channel closing appears to be the main intra-SR buffer, calsequestrin (CSQ) (9).By contrast, in skeletal muscle, depletion associated with a twitch is only 8-15% (10). This low rate of depletion reflects a SR with larger terminal cisternae containing higher concentrations of a CSQ of greater binding capacity, thus constituting a much greater calcium reservoir. Despite the greater store, sparks of skeletal mus...

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Transfer and Tunneling of Ca2+ from Sarcoplasmic Reticulum to Mitochondria in Skeletal Muscle

Cited by 88 publications

References 29 publications

Mitochondria Are Linked to Calcium Stores in Striated Muscle by Developmentally Regulated Tethering Structures

Mitochondria Are Linked to Calcium Stores in Striated Muscle by Developmentally Regulated Tethering Structures

Physical Coupling Supports the Local Ca2+ Transfer between Sarcoplasmic Reticulum Subdomains and the Mitochondria in Heart Muscle

Depletion “skraps” and dynamic buffering inside the cellular calcium store

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