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J. Biol. Chem., Vol. 280, Issue 1, 715-721, January 7, 2005

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[Ca²⁺]_i Signaling between Mitochondria and Endoplasmic Reticulum in Neurons Is Regulated by Microtubules

FROM MITOCHONDRIAL PERMEABILITY TRANSITION PORE TO Ca²⁺-INDUCED Ca²⁺ RELEASE^*

Sergej L. Mironov, Maxim V. Ivannikov, and Mattias Johansson

From the Institute for Physiology, Georg August University, Humboldtallee 23, 37073 Göttingen, Germany

The positioning and dynamics of organelles depend on membrane-cytoskeleton interactions. Mitochondria relocate along microtubules (MT), but it is not clear whether MT have direct effects on mitochondrial function. Using two-photon microscopy and the mitochondrial fluorescent dyes rhodamine 123 and Rhod-2, we showed that Taxol and nocodazole, which correspondingly stabilize and disrupt MT, decreased potential and Ca²⁺ in the mitochondria of brain stem pre-Bötzinger complex neurons. Without changing basal cytoplasmic Ca²⁺ ([Ca²⁺]_i), Taxol promoted the generation of [Ca²⁺]_i spikes in dendrites. These spikes were abolished after blockade of Ca²⁺ influx and after depletion of internal Ca²⁺ stores, indicating the involvement of Ca²⁺-induced Ca²⁺ release. Nocodazole decreased mitochondrial potential and [Ca²⁺]_m and produced a long lasting increase in [Ca²⁺]_i. MT-acting drugs depolarized single immobilized mitochondria and released previously stored Ca²⁺. All of these effects were inhibited by pretreatment with blockers of mitochondrial permeability transition pore (mPTP), cyclosporin A, and 2-aminoethoxydiphenyl borate. Induction of mPTP by Taxol and nocodazole was confirmed by using a calcein/Co²⁺ imaging technique. Electron and optical microscopy revealed tubulin bound to mitochondria. Mitochondria, MT, and endoplasmic reticulum (ER) showed strong co-localization, the degree of which decreased after MT were disrupted. We propose that changes in the structure of MT by Taxol and nocodazole promote the induction of mPTP. Subsequent Ca²⁺ efflux stimulates the Ca²⁺ release from the ER that drives spontaneous [Ca²⁺]_i transients. Thus, close positioning of mitochondria to the ER as determined by MT can be essential for the local [Ca]_i signaling in neurons.

Received for publication, August 26, 2004 , and in revised form, October 27, 2004.

^* The study was supported by Deutsche Forschungsgemeinschaft via the Center of Molecular Physiology of the Brain and by Graduiertenkollegs (GRK 723). 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.

To whom correspondence should be addressed: Dept. of Neuro- and Sensory Physiology, Georg August University, Humboldtallee 23, 37073 Göttingen, Germany. Tel./Fax: 49-551-39-59-17; E-mail: slm{at}ukps.gwdg.de.

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