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CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology.

ABSTRACT: 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 Ialpha (CaMKIalpha). 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. CaMKIalpha 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.

SUBMITTER: Han XJ

PROVIDER: S-EPMC2500141 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology.

Han Xiao-Jian XJ Lu Yun-Fei YF Li Shun-Ai SA Kaitsuka Taku T Sato Yasufumi Y Tomizawa Kazuhito K Nairn Angus C AC Takei Kohji K Matsui Hideki H Matsushita Masayuki M

The Journal of cell biology 20080801 3

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-assoc ...[more]

PMID: 18695047

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Project description:BackgroundCancer-associated cachexia (CAC) is a syndrome characterized by skeletal muscle atrophy, and the underlying mechanisms are still unclear. Recent research studies have shed light on a noteworthy link between mitochondrial dynamics and muscle physiology. In the present study, we investigate the role of dynamin-related protein 1 (DRP1), a pivotal factor of mitochondrial dynamics, in myotube atrophy during cancer-associated cachexia.MethodsSeventy-six surgical patients, including gastrointestinal tumor and benign disease, were enrolled in the study and divided to three groups: control, non-cachexia, and cancer-associated cachexia. Demographic data were collected. Their rectus abdominis samples were acquired intraoperatively. Muscle fiber size, markers of ubiquitin proteasome system (UPS), mitochondrial ultrastructure, and markers of mitochondrial function and dynamics were assayed. A cachexia model in vitro was established via coculturing a C2C12 myotube with media from C26 colon cancer cells. A specific DRP1 inhibitor, Mdivi-1, and a lentivirus of DRP1 knockdown/overexpression were used to regulate the expression of DRP1. Muscle diameter, mitochondrial morphology, mass, reactive oxygen species (ROS), membrane potential, and markers of UPS, mitochondrial function, and dynamics were determined.ResultsPatients of cachexia suffered from a conspicuous worsened nutrition status and muscle loss compared to patients of other groups. Severe mitochondrial swelling and enlarged area were observed, and partial alterations in mitochondrial function were found in muscle. Analysis of mitochondrial dynamics indicated an upregulation of phosphorylated DRP1 at the ser616 site. In vitro, cancer media resulted in the atrophy of myotube. This was accompanied with a prominent unbalance of mitochondrial dynamics, as well as enhanced mitochondrial ROS and decreased mitochondrial function and membrane potential. However, certain concentrations of Mdivi-1 and DRP1 knockdown rebalanced the mitochondrial dynamics, mitigating this negative phenotype caused by cachexia. Moreover, overexpression of DRP1 aggravated these phenomena.ConclusionIn clinical patients, cachexia induces abnormal mitochondrial changes and possible fission activation for the atrophied muscle. Our cachexia model in vitro further demonstrates that unbalanced mitochondrial dynamics contributes to this atrophy and mitochondrial impairment, and rebuilding the balance by regulating of DRP1 could ameliorate these alterations.

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CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology.

Publications

CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology.

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