Large-scale RNAi Screen Identified Dhpr As A Regulator Of Mitochondrial Morphology And Tissue Homeostasis

Mitochondria are highly dynamic organelles that keep changing their shapes through fusion and fission.Mutations in multiple key molecules regulating mitochondrial morphology could lead to severe human diseases.However,how mitochondrial morphology is regulated is still not fully understood.Through a large-scale in vivo RNAi screening that covered around a quarter of the Drosophila melanogester genome(4000 genes),we identified 578 genes whose knockdown led to aberrant shapes or distributions of mitochondria.The complex analysis revealed that the knockdown of the subunits of proteasomes and spliceosomes could severely affect mitochondrial morphology.Interestingly,many hits encoded mitochondrial proteins.In addition,we found that enzymes regulating tyrosine metabolism and lysine degradation are critical to maintain proper mitochondrial morphology.We identified a gene encoding Dhpr,whose reduction could lead to mitochondrial morphology changes that are very similar to those in the tissues with Parkinson's disease-related genes Pinkl and park reduction.The affected mitochondria in Dhpr mutants were swollen and had less cristae.Further analysis revealed that the loss of Dhpr could lead to the reduction in the numbers of TH neurons,shorter lifespan,and gradual loss of muscle integrity and climbing ability.The mitochondrial defects caused by the loss of Dhpr could be partially rescued by Pinkl and park overexpression.The enzyme activity of Dhpr is critical for mitochondrial function.The reduction of nitric oxide synthesis could enhance Dhpr RNAi-induced mitochondrial defects.The reduction of Dhpr could reduce the Drpl S-nitrosylation level.Overexpression of Drpl,but not S-nitrosylation defective Drpl,could rescue Dhpr RNAi-induced mitochondrial defects.We propose a model that Dhpr could regulate mitochondrial morphology and tissue homeostasis via modulating S-nitrosylation of Drpl.