Inhibition Of Mitochondrial Fusion Rescues Phenotypes Resulted From Suppression Of Autophagy In Drosophila Neuron

Macroautophagy (hereafter referred to autophagy) is an evolutionarily conserved major intracellular catabolic process, in which double-membrane autophagosomes sequester organelles or proteins and transport to lysosomes. Autophagosomes ultimately fuse with lysosomes to form autolysosomes, where their contents are degraded to generate new building blocks and energy for cellular renovation and homeostasis. Neurons are highly differentiated cells. Cellular quality control through autophagy is particularly relevant in neurons, where the total content of altered proteins and damaged organelles can’t be reduced by redistribution to daughter cells by means of cell division. A growing body of evidence directly links alterations of the autophagic system to many kinds of neurodegenerative disorders, such as Parkinson’s diseases (PD). But mechanism behind autophagic failure in degenerating neurons remains unclear.In a previous study, we have found that knockdown of either Atg5or Atgl2in Drosophila neurons causes abnormal wing and thorax phenotypes. In this study, we have found that Da-gal4driven whole body knockdown of Atg5or Atg12leads to defective phenotypes similar to those in pan-neuronal knockdown of the genes. Moreover, knockdown of Atg5or Atg12inhibits starve-induced autophagy in fat-body. Furthermore, knockdown of mitochondrial fusion gene Marf rescues phenotypes induced by knockdown of Atg5or Atg12. In contrast, overexpression of hOPAl further exacerbates the phenotypes induced by knockdown of Atg5. The study suggests that autophagy regulated mitochondrial homeostasis likely play an important role in neurodegeneration.