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J. Biol. Chem., Vol. 282, Issue 48, 34839-34849, November 30, 2007

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Early Developmental Pathology Due to Cytochrome c Oxidase Deficiency Is Revealed by a New Zebrafish Model^*

Katrina N. Baden, James Murray, Roderick A. Capaldi, and Karen Guillemin¹

From the Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403-1229 and MitoSciences Inc., Eugene, Oregon 97403-2095

Deficiency of cytochrome c oxidase (COX) is associated with significant pathology in humans. However, the consequences for organogenesis and early development are not well understood. We have investigated these issues using a zebrafish model. COX deficiency was induced using morpholinos to reduce expression of CoxVa, a structural subunit, and Surf1, an assembly factor, both of which impaired COX assembly. Reduction of COX activity to 50% resulted in developmental defects in endodermal tissue, cardiac function, and swimming behavior. Cellular investigations revealed different underlying mechanisms. Apoptosis was dramatically increased in the hindbrain and neural tube, and secondary motor neurons were absent or abnormal, explaining the motility defect. In contrast, the heart lacked apoptotic cells but showed increasingly poor performance over time, consistent with energy deficiency. The zebrafish model has revealed tissue-specific responses to COX deficiency and holds promise for discovery of new therapies to treat mitochondrial diseases in humans.

Received for publication, April 27, 2007 , and in revised form, August 6, 2007.

^* This work was supported by National Institutes of Health (NIH) Grants R21 DK067065-01 (to K. G.) and RO1 DK075549-01 (to K. G.) and The Eugene and Clarissa Evonuk Memorial Graduate Fellowship in Environmental or Stress Physiology (to K. B.). NIH Grant HD22486 provided support for the Oregon Zebrafish Facility. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental supplemental Fig. S1 and Movies S1 and S2.

¹ To whom correspondence should be addressed: University of Oregon, 1370 Franklin Blvd., Eugene, OR 97403-2095. Tel.: 541-346-5360; Fax: 541-346-5891; E-mail: guillemin{at}molbio.uoregon.edu.

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