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

• Published in: The Journal of biological chemistry Vol. 282; no. 48; pp. 34839 - 34849
• Main Authors: Baden, Katrina N., Murray, James, Capaldi, Roderick A., Guillemin, Karen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30-11-2007; American Society for Biochemistry and Molecular Biology
• Subjects: Acridine Orange - pharmacology; Animals; Apoptosis; Cytochrome-c Oxidase Deficiency - genetics; Danio rerio; DNA, Mitochondrial - metabolism; Electron Transport Complex IV - genetics; Electron Transport Complex IV - physiology; Freshwater; Gene Expression Regulation, Developmental; Heart - embryology; Heart - physiology; Humans; Immunohistochemistry - methods; Motor Neurons - metabolism; Myocardium - metabolism; Neural Tube - embryology; Phenotype; Time Factors; Zebrafish
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M703528200

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.