Multi-organ Abnormalities and mTORC1 Activation in Zebrafish Model of Multiple Acyl-CoA Dehydrogenase Deficiency

Multiple acyl-coa dehydrogenase deficiency (madd) is a severe mitochondrial disorder featuring multi-organ dysfunction. mutations in either the etfa,etfb,and etfdh genes can cause madd but very little is known about disease specific mechanisms due to a paucity of animal models. we report a novel zebrafish mutant dark xavier (dxavu463) that has an inactivating mutation in the etfa gene. dxavu463 recapitulates numerous pathological and biochemical features seen in patients with madd including brain,liver,and kidney disease. similar to children with madd,homozygote mutant dxavu463 zebrafish have a spectrum of phenotypes ranging from moderate to severe. interestingly,excessive maternal feeding significantly exacerbated the phenotype. homozygous mutant dxavu463 zebrafish have swollen and hyperplastic neural progenitor cells,hepatocytes and kidney tubule cells as well as elevations in triacylglycerol,cerebroside sulfate and cholesterol levels. their mitochondria were also greatly enlarged,lacked normal cristae,and were dysfunctional. we also found increased signaling of the mechanistic target of rapamycin complex 1 (mtorc1) with enlarged cell size and proliferation. treatment with rapamycin partially reversed these abnormalities. our results indicate that etfa gene function is remarkably conserved in zebrafish as compared to humans with highly similar pathological,biochemical abnormalities to those reported in children with madd. altered mtorc1 signaling and maternal nutritional status may play critical roles in madd disease progression and suggest novel treatment approaches that may ameliorate disease severity. © 2013 kim et al.