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J. Biol. Chem., Vol. 283, Issue 18, 12333-12342, May 2, 2008

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Mitochondrial Transcription Factor B2 Is Essential for Metabolic Function in Drosophila melanogaster Development^*

Cristina Adán¹, Yuichi Matsushima, Rosana Hernández-Sierra, Raquel Marco-Ferreres¹, Miguel Ángel Fernández-Moreno, Emiliano González-Vioque², Manuel Calleja^¶, Juan J. Aragón, Laurie S. Kaguni, and Rafael Garesse³

From the Departamento de Bioquímica, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, CIBERER ISCIII, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, E-28029 Madrid, Spain, the Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824-1319, and the ^¶Centro de Biología Molecular "Severo Ochoa" CSIC-UAM, Universidad Autónoma de Madrid, 28049 Madrid, Spain

Characterization of the basal transcription machinery of mitochondrial DNA (mtDNA) is critical to understand mitochondrial pathophysiology. In mammalian in vitro systems, mtDNA transcription requires mtRNA polymerase, transcription factor A (TFAM), and either transcription factor B1 (TFB1M) or B2 (TFB2M). We have silenced the expression of TFB2M by RNA interference in Drosophila melanogaster. RNA interference knockdown of TF2BM causes lethality by arrest of larval development. Molecular analysis demonstrates that TF2BM is essential for mtDNA transcription during Drosophila development and is not redundant with TFB1M. The impairment of mtDNA transcription causes a dramatic decrease in oxidative phosphorylation and mitochondrial ATP synthesis in the long-lived larvae, and a metabolic shift to glycolysis, which partially restores ATP levels and elicits a compensatory response at the nuclear level that increases mitochondrial mass. At the cellular level, the mitochondrial dysfunction induced by TFB2M knockdown causes a severe reduction in cell proliferation without affecting cell growth, and increases the level of apoptosis. In contrast, cell differentiation and morphogenesis are largely unaffected. Our data demonstrate the essential role of TFB2M in mtDNA transcription in a multicellular organism, and reveal the complex cellular, biochemical, and molecular responses induced by impairment of oxidative phosphorylation during Drosophila development.

Received for publication, February 20, 2008

^* This work was supported in part by Ministerio de Educación y Ciencia, Spain, Grants BFU2004-04591 (to R. G.) and BFU2005-09071 (to J. J. A.), Instituto de Salud Carlos III, Redes de centros RCMN Grant C03/08 (to R. G. and J. J. A.), Temáticas Grant G03/011 (to R. G.), the Centro de Investigación Biomédica en Red de Enfermedades Raras, and National Institutes of Health Grant GM45295 (to L. S. K.). 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.

¹ Recipients of predoctoral fellowships from the Ministerio de Educación y Ciencia, Spain.

² Recipient of a predoctoral fellowship from the Instituto de Salud Carlos III, Spain.

³ To whom correspondence should be addressed. Tel.: 34-91-4975452; Fax: 34-91-5854401; E-mail: rafael.garesse{at}uam.es.

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