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J. Biol. Chem., Vol. 279, Issue 30, 31544-31555, July 23, 2004

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Knockdown of MTP18, a Novel Phosphatidylinositol 3-Kinase-dependent Protein, Affects Mitochondrial Morphology and Induces Apoptosis^*

Daniel Tondera, Ansgar Santel, Rolf Schwarzer, Sybille Dames, Klaus Giese, Anke Klippel, and Jörg Kaufmann

From the Atugen AG, Otto Warburg Haus (Nr. 80), Robert-Rössle-Strasse 10, 13125 Berlin, Germany

We identified a novel human cDNA encoding a mitochondrial protein, MTP18 (mitochondrial protein, 18 kDa) as a transcriptional downstream target of phosphatidylinositol (PI) 3-kinase signaling. We demonstrate that MTP18 mRNA as well as protein expression is dependent on PI 3-kinase activity. Confocal microscopy and biochemical fractionation revealed a mitochondrial localization of MTP18. Loss-of-function analysis employing antisense molecules revealed that MTP18 is essential for cell viability in PC-3 and HaCaT cells. We show that knockdown of MTP18 protein level results in a cytochrome c release from mitochondria and consequently leads to apoptosis. In addition, HaCaT cells with reduced levels of MTP18 become more sensitive to apoptotic stimuli. This effect is accompanied by dramatic subcellular alterations. Reduction of MTP18 impairs mitochondrial morphology resulting in the formation of a highly interconnected mitochondrial reticulum in COS-7 cells. Conversely, overexpression of MTP18 induces a punctuate morphology of mitochondria suggesting also a functional role of MTP18 in maintaining the mitochondrial integrity. Hence, our data indicate an unexpected connection of PI 3-kinase signaling, apoptosis and the morphology of mammalian mitochondria.

Received for publication, April 28, 2004 , and in revised form, May 19, 2004.

^* This work was supported by a grant from the Bundesministerium für Wirtschaft und Technologie (No. 1078/02). 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. Tel.: 49-30-9489-2833; Fax: 49-30-9489-2801; E-mail: kaufmann{at}atugen.com.

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