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CaM kinase I–induced phosphorylation of Drp1 regulates mitochondrial morphology

¹ Department of Physiology and ² Department of Neuroscience, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan
³ Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508
⁴ Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan

Correspondence to Masayuki Matsushita: masayuki{at}mitils.jp

Mitochondria are dynamic organelles that frequently move, divide, and fuse with one another to maintain their architecture and functions. However, the signaling mechanisms involved in these processes are still not well characterized. In this study, we analyze mitochondrial dynamics and morphology in neurons. Using time-lapse imaging, we find that Ca²⁺ influx through voltage-dependent Ca²⁺ channels (VDCCs) causes a rapid halt in mitochondrial movement and induces mitochondrial fission. VDCC-associated Ca²⁺ signaling stimulates phosphorylation of dynamin-related protein 1 (Drp1) at serine 600 via activation of Ca²⁺/calmodulin-dependent protein kinase I (CaMKI). In neurons and HeLa cells, phosphorylation of Drp1 at serine 600 is associated with an increase in Drp1 translocation to mitochondria, whereas in vitro, phosphorylation of Drp1 results in an increase in its affinity for Fis1. CaMKI is a widely expressed protein kinase, suggesting that Ca²⁺ is likely to be functionally important in the control of mitochondrial dynamics through regulation of Drp1 phosphorylation in neurons and other cell types.

Abbreviations used in this paper: ANOVA, analysis of variance; CaMK, Ca²⁺/calmodulin-dependent protein kinase; CaMKI-CA, constitutively active CaMKI; CaMKI-DN, dominant-negative CaMKI; DIV, days in vitro; Drp1, dynamin-related protein 1; GED, GTPase effector domain; VDCC, voltage-dependent Ca²⁺ channel.

© 2008 Han et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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