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

摘要: 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 known about disease specific mechanisms due to paucity of animal models. We report novel zebrafish mutant dark xavier (dxavu463) that has an inactivating mutation etfa gene. dxavu463 recapitulates numerous pathological biochemical features seen patients with including brain, liver, kidney disease. Similar children MADD, homozygote have spectrum phenotypes ranging from moderate severe. Interestingly, excessive maternal feeding significantly exacerbated phenotype. Homozygous swollen hyperplastic neural progenitor cells, hepatocytes tubule cells as well elevations triacylglycerol, cerebroside sulfate cholesterol levels. Their mitochondria were also greatly enlarged, lacked normal cristae, dysfunctional. found increased signaling mechanistic target rapamycin complex 1 (mTORC1) enlarged cell size proliferation. Treatment partially reversed these abnormalities. Our results indicate gene function remarkably conserved compared humans highly similar pathological, abnormalities those reported MADD. Altered mTORC1 nutritional status may play critical roles progression suggest treatment approaches ameliorate severity.