REVIEW ARTICLE Zebrafish as a model system for mitochondrial biology and diseases: a review Q29 S. L. STEELE, S. V. PRYKHOZHIJ, and JASON N. BERMAN Q1 HALIFAX, NOVA SCOTIA, CANADA Animal models for studying human disease are essential to the continuing evolution of medicine. Rodent models are attractive for the obvious similarities in development and genetic makeup compared with humans, but have cost and technical limita- tions. The zebrafish (Danio rerio) represents an excellent alternative vertebrate model of human disease because of its high conservation of genetic information and physiological processes, inexpensive maintenance, and optical clarity facilitat- ing direct observation. This review highlights recent advances in understanding ge- netic disease states associated with the dynamic organelle, the mitochondrion, using zebrafish. Mitochondrial diseases that have been replicated in the zebrafish in- clude those affecting the nervous and cardiovascular systems, as well as red blood cell function. There are a large number of studies involving genes associated with Parkinson’s disease, as well as many of the genes associated with heme synthesis and anemia. Gene silencing techniques, including morpholino knockdown and TAL Q2 -effector endonucleases have been exploited to demonstrate how loss of func- tion can induce human diseaselike states in zebrafish. Moreover, modeling mito- chondrial diseases has been facilitated greatly by the creation of transgenic fish with fluorescently labeled mitochondria for in vivo visualization of these structures. In addition, behavioral assays have been developed to examine changes in motor activity and sensory responses, particularly in larval stages. Zebrafish are poised to advance our understanding of the pathogenesis of human mitochondrial diseases beyond the current state of knowledge and provide a key tool in the development of novel therapeutic approaches to treat these conditions. (Translational Research 2013;-:1–20) Abbreviations: 2,5-DHBA ¼ 2,5-dihydroxybenzoic acid; ALS ¼ amyotrophic lateral sclerosis; ATP ¼ adenosine triphosphate; Bcl-2 ¼ B-cell lymphoma 2; CMT2 ¼ Charcot-Marie-Tooth 2; CNS ¼ central nervous system; COX ¼ cytochrome c oxidase; DA ¼ dopaminergic; ETFDH ¼ electron transfer flavoprotein dehydrogenase; HIF1a ¼ hypoxia-induced factor 1a; hpf ¼ hours postfertilization; HSC ¼ hematopoietic stem cell; IMM ¼ inner mitochondrial membrane; From the Department of Pediatrics, Dalhousie University, IWK Health Centre, Halifax, Nova Scotia, Canada. Conflicts of Interest: All authors have read the journal’s policy on dis- closure of conflict of interest and have nothing to declare. S. L. Steele is funded by the Genome Canada IGNITE Project (Iden- tifying Genes and Novel Therapeutics to Enhance Treatment). S. V. Prykhozhij is funded by the Genome Canada IGNITE Project (Identi- fying Genes and Novel Therapeutics to Enhance Treatment) and the Canadian Institutes for Health Research (application no. 287512). S. L. Steele and S. V. Prykhozhij contributed equally to this work. Submitted for publication June 24, 2013; revision submitted August 21, 2013; accepted for publication August 25, 2013. Reprint requests: Jason N. Berman, IWK Health Centre, PO Box 9700, 5850/5980 University Avenue, Halifax, NS, B3K 6R8, Canada; e-mail: jason.berman@iwk.nshealth.ca. 1931-5244/$ - see front matter Ó 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.trsl.2013.08.008 1 REV 5.2.0 DTD  TRSL691_proof  19 September 2013  6:40 pm  ce 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127