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Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit.

Yi M, Weaver D, Hajnóczky G - J. Cell Biol. (2004)

Bottom Line: By clamping cytoplasmic [Ca2+] ([Ca2+]c) at various levels, mitochondrial motility was found to be regulated by Ca2+ in the physiological range.The inositol 1,4,5-trisphosphate- or ryanodine receptor-mediated [Ca2+]c signal also induced a decrease in mitochondrial motility.This decrease followed the spatial and temporal pattern of the [Ca2+]c signal.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

ABSTRACT
Mitochondria are dynamic organelles in cells. The control of mitochondrial motility by signaling mechanisms and the significance of rapid changes in motility remains elusive. In cardiac myoblasts, mitochondria were observed close to the microtubular array and displayed both short- and long-range movements along microtubules. By clamping cytoplasmic [Ca2+] ([Ca2+]c) at various levels, mitochondrial motility was found to be regulated by Ca2+ in the physiological range. Maximal movement was obtained at resting [Ca2+]c with complete arrest at 1-2 microM. Movement was fully recovered by returning to resting [Ca2+]c, and inhibition could be repeated with no apparent desensitization. The inositol 1,4,5-trisphosphate- or ryanodine receptor-mediated [Ca2+]c signal also induced a decrease in mitochondrial motility. This decrease followed the spatial and temporal pattern of the [Ca2+]c signal. Diminished mitochondrial motility in the region of the [Ca2+]c rise promotes recruitment of mitochondria to enhance local Ca2+ buffering and energy supply. This mechanism may provide a novel homeostatic circuit in calcium signaling.

Show MeSH
Decoding of [Ca2+]c signals by the mitochondrial motor machinery. The proposed mechanism for the [Ca2+]c signal-dependent control of mitochondrial motility is shown.
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fig6: Decoding of [Ca2+]c signals by the mitochondrial motor machinery. The proposed mechanism for the [Ca2+]c signal-dependent control of mitochondrial motility is shown.

Mentions: The scheme in Fig. 6 and the animation in Video 3 (available at http://www.jcb.org/cgi/content/full/jcb.200406038/DC1) show the mechanism of the Ca2+-dependent control of mitochondrial movement determined in the present work. At resting [Ca2+]c (Fig. 6, left), mitochondria display maximal movement activity and the majority of the movements occur along the MTs (Fig. 6 left, arrows). Movements of the mitochondria toward the plus end are promoted by kinesin motors, whereas movements to the minus end are facilitated by dynein motor proteins (Tanaka et al., 1998; Habermann et al., 2001; Deacon et al., 2003; Varadi et al., 2004). When a [Ca2+]c rise occurs due to either Ca2+ mobilization or Ca2+ entry, the mitochondrial movement decreases. Even a modest increase in [Ca2+]c is sufficient to attenuate mitochondrial motility and the elevation of global [Ca2+]c to 1 μM, a level that is commonly attained during [Ca2+]c spikes and oscillations results in almost complete loss of mitochondrial movement (Video 3, right panel). Ca2+ does not seem to activate Ca2+/CaM-dependent kinases or the Ca2+-dependent protein phosphatase to establish control over mitochondrial motility because several inhibitors of these enzymes failed to interfere with the movement inhibition by Ca2+. Furthermore, Ca2+ does not seem to target directly the microtubular motors because the molecular structure of mammalian cytoplasmic dynein and kinesin does not indicate the presence of a site for binding of Ca2+ or CaM (Vale, 2003). Thus, we propose that a distinct Ca2+ sensor molecule is required to translate the Ca2+ signal for the microtubular motor proteins. Binding of Ca2+ to the Ca2+ sensor would induce the MT-bound motors to lock in a stationary position or to detach from the MTs (Video 3, red symbol). One potential candidate for the Ca2+ sensor is myosin Va, a motor protein that binds CaM and is controlled by Ca2+ (for reviews see Reck-Peterson et al., 2000; Vale, 2003). Myosin Va displays a Ca2+-dependent interaction with actin-filaments (Tauhata et al., 2001; Krementsov et al., 2004) and MTs (Cao et al., 2004). Interaction of the head domain of myosin Va with actin provides a motor for movement along the MFs but the tail domain-based interaction with MTs does not present by itself a microtubular motor. However, recent papers have raised the possibility that myosin V can interact directly with dynein and kinesin and through this interaction may affect motor function at the MTs (Benashski et al., 1997; Huang et al., 1999; Stafford et al., 2000; Lalli et al., 2003). Immunocytochemistry studies indicate that myosin Va is present on the mitochondria in H9c2 cells, and myosin Va is also retained on isolated mitochondria (unpublished data). However, to clarify the role of myosin V in the Ca2+-dependent control of mitochondrial motility and to explore alternative mechanisms, further studies are needed.


Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit.

Yi M, Weaver D, Hajnóczky G - J. Cell Biol. (2004)

Decoding of [Ca2+]c signals by the mitochondrial motor machinery. The proposed mechanism for the [Ca2+]c signal-dependent control of mitochondrial motility is shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172592&req=5

fig6: Decoding of [Ca2+]c signals by the mitochondrial motor machinery. The proposed mechanism for the [Ca2+]c signal-dependent control of mitochondrial motility is shown.
Mentions: The scheme in Fig. 6 and the animation in Video 3 (available at http://www.jcb.org/cgi/content/full/jcb.200406038/DC1) show the mechanism of the Ca2+-dependent control of mitochondrial movement determined in the present work. At resting [Ca2+]c (Fig. 6, left), mitochondria display maximal movement activity and the majority of the movements occur along the MTs (Fig. 6 left, arrows). Movements of the mitochondria toward the plus end are promoted by kinesin motors, whereas movements to the minus end are facilitated by dynein motor proteins (Tanaka et al., 1998; Habermann et al., 2001; Deacon et al., 2003; Varadi et al., 2004). When a [Ca2+]c rise occurs due to either Ca2+ mobilization or Ca2+ entry, the mitochondrial movement decreases. Even a modest increase in [Ca2+]c is sufficient to attenuate mitochondrial motility and the elevation of global [Ca2+]c to 1 μM, a level that is commonly attained during [Ca2+]c spikes and oscillations results in almost complete loss of mitochondrial movement (Video 3, right panel). Ca2+ does not seem to activate Ca2+/CaM-dependent kinases or the Ca2+-dependent protein phosphatase to establish control over mitochondrial motility because several inhibitors of these enzymes failed to interfere with the movement inhibition by Ca2+. Furthermore, Ca2+ does not seem to target directly the microtubular motors because the molecular structure of mammalian cytoplasmic dynein and kinesin does not indicate the presence of a site for binding of Ca2+ or CaM (Vale, 2003). Thus, we propose that a distinct Ca2+ sensor molecule is required to translate the Ca2+ signal for the microtubular motor proteins. Binding of Ca2+ to the Ca2+ sensor would induce the MT-bound motors to lock in a stationary position or to detach from the MTs (Video 3, red symbol). One potential candidate for the Ca2+ sensor is myosin Va, a motor protein that binds CaM and is controlled by Ca2+ (for reviews see Reck-Peterson et al., 2000; Vale, 2003). Myosin Va displays a Ca2+-dependent interaction with actin-filaments (Tauhata et al., 2001; Krementsov et al., 2004) and MTs (Cao et al., 2004). Interaction of the head domain of myosin Va with actin provides a motor for movement along the MFs but the tail domain-based interaction with MTs does not present by itself a microtubular motor. However, recent papers have raised the possibility that myosin V can interact directly with dynein and kinesin and through this interaction may affect motor function at the MTs (Benashski et al., 1997; Huang et al., 1999; Stafford et al., 2000; Lalli et al., 2003). Immunocytochemistry studies indicate that myosin Va is present on the mitochondria in H9c2 cells, and myosin Va is also retained on isolated mitochondria (unpublished data). However, to clarify the role of myosin V in the Ca2+-dependent control of mitochondrial motility and to explore alternative mechanisms, further studies are needed.

Bottom Line: By clamping cytoplasmic [Ca2+] ([Ca2+]c) at various levels, mitochondrial motility was found to be regulated by Ca2+ in the physiological range.The inositol 1,4,5-trisphosphate- or ryanodine receptor-mediated [Ca2+]c signal also induced a decrease in mitochondrial motility.This decrease followed the spatial and temporal pattern of the [Ca2+]c signal.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

ABSTRACT
Mitochondria are dynamic organelles in cells. The control of mitochondrial motility by signaling mechanisms and the significance of rapid changes in motility remains elusive. In cardiac myoblasts, mitochondria were observed close to the microtubular array and displayed both short- and long-range movements along microtubules. By clamping cytoplasmic [Ca2+] ([Ca2+]c) at various levels, mitochondrial motility was found to be regulated by Ca2+ in the physiological range. Maximal movement was obtained at resting [Ca2+]c with complete arrest at 1-2 microM. Movement was fully recovered by returning to resting [Ca2+]c, and inhibition could be repeated with no apparent desensitization. The inositol 1,4,5-trisphosphate- or ryanodine receptor-mediated [Ca2+]c signal also induced a decrease in mitochondrial motility. This decrease followed the spatial and temporal pattern of the [Ca2+]c signal. Diminished mitochondrial motility in the region of the [Ca2+]c rise promotes recruitment of mitochondria to enhance local Ca2+ buffering and energy supply. This mechanism may provide a novel homeostatic circuit in calcium signaling.

Show MeSH