title: The cellular and molecular progression of mitochondrial dysfunction induced by 2,4-dinitrophenol in developing zebrafish embryos.
abstract: The etiology of mitochondrial disease is poorly understood. Furthermore, treatment options are limited, and diagnostic methods often lack the sensitivity to detect disease in its early stages. Disrupted oxidative phosphorylation (OXPHOS) that inhibits ATP production is a common phenotype of mitochondrial disorders that can be induced in zebrafish by exposure to 2,4-dinitrophenol (DNP), a FDA-banned weight-loss agent and EPA-regulated environmental toxicant, traditionally used in research labs as an uncoupler of OXPHOS. Despite the DNP-induced OXPHOS inhibition we observed using in vivo respirometry, the development of the DNP-treated and control zebrafish were largely similar during the first half of embryogenesis. During this period, DNP-treated embryos induced gene expression of mitochondrial and nuclear genes that stimulated the production of new mitochondria and increased glycolysis to yield normal levels of ATP. DNP-treated embryos were incapable of sustaining this mitochondrial biogenic response past mid-embryogenesis, as shown by significantly lowered ATP production and ATP levels, decreased gene expression, and the onset of developmental defects. Examining neural tissues commonly affected by mitochondrial disease, we found that DNP exposure also inhibited motor neuron axon arbor outgrowth and the proper formation of the retina. We observed and quantified the molecular and physiological progression of mitochondrial dysfunction during development with this new model of OXPHOS dysfunction, which has great potential for use in diagnostics and therapies for mitochondrial disease.
authors.affiliation: Medical University of South Carolina, Drug Discovery & Biomedical Sciences, 280 Calhoun Street, MSC 140, QE 219A, Charleston, SC 29425, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Bestman
authors.affiliation: Medical University of South Carolina, Drug Discovery & Biomedical Sciences, 280 Calhoun Street, MSC 140, QE 219A, Charleston, SC 29425, USA.
authors.forename: Krista D
authors.initials: KD
authors.lastname: Stackley
authors.affiliation: Medical University of South Carolina, Drug Discovery & Biomedical Sciences, 280 Calhoun Street, MSC 140, QE 219A, Charleston, SC 29425, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Rahn
authors.affiliation: Medical University of South Carolina, Drug Discovery & Biomedical Sciences, 280 Calhoun Street, MSC 140, QE 219A, Charleston, SC 29425, USA.
authors.forename: Tucker J
authors.initials: TJ
authors.lastname: Williamson
authors.affiliation: Medical University of South Carolina, Drug Discovery & Biomedical Sciences, 280 Calhoun Street, MSC 140, QE 219A, Charleston, SC 29425, USA. Electronic address: chans@musc.edu.
authors.forename: Sherine S L
authors.initials: SS
authors.lastname: Chan
mesh_terms: D019297:2,4-Dinitrophenol / Q000633:toxicity; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D047108:Embryonic Development / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D012160:Retina / Q000378:metabolism / Q000473:pathology; D015027:Zebrafish
chemical_list: D000255:Adenosine Triphosphate; D019297:2,4-Dinitrophenol
keywords: Embryo; Energy metabolism; In vivo respirometry; Motor neuron; Retina; Zebrafish