Modulation of mitochondrial metabolic function by phorbol 12-myristate 13-acetate through increased mitochondrial translocation of protein kinase Cα in C2C12 myocytes

被引:33
作者
Wang, Ying
Biswas, Gopa
Prabu, Subbuswamy K.
Avadhani, Narayan G. [1 ]
机构
[1] Univ Penn, Sch Vet Med, Dept Anim Biol, Labs Biochem, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Vet Med, Mari Lowe Ctr Comparat Oncol, Philadelphia, PA 19104 USA
关键词
D O I
10.1016/j.bcp.2006.06.032
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Protein kinase C (PKC) agonists including phorbol 12-myristate 13-acetate (PMA) not only induce the redistribution of cytosolic PKC to various subcellular compartments but also activate the kinase domain of the protein. In the present study we have investigated the nature of mitochondrial PKC pool and its effects on mitochondrial function in cells treated with PMA. Treatment of C2C12 myoblasts, C6 glioma and COS7 cells with PMA resulted in a dramatic redistribution of intracellular PKC(x pool, with large fraction of the protein pool sequestered in the mitochondrial compartment. We also observed mitochondrial PKC delta accumulation in a cell restricted manner. The intramitochondrial localization was ascertained by using a combination of protection against protease treatment of isolated mitochondria. and immunofluorescence microscopy. PMA-induced mitochondrial localization of PKC alpha was accompanied by increased mitochondrial PKC activity, altered cell morphology, disruption of mitochondrial membrane potential, decreased complex I and pyruvate dehydrogenase activities, and increased mitochondrial ROS production. All of these changes could be retarded by treatment with PKC inhibitors. These results show a direct role for PMA-mediated PKC alpha translocation to mitochondria in inducing mitochondrial toxicity. (c) 2006 Elsevier Inc. All rights reserved.
引用
收藏
页码:881 / 892
页数:12
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