Research ArticleCELL BIOLOGY

Large-scale RNAi screen identified Dhpr as a regulator of mitochondrial morphology and tissue homeostasis

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Science Advances  18 Sep 2019:
Vol. 5, no. 9, eaax0365
DOI: 10.1126/sciadv.aax0365

Abstract

Mitochondria are highly dynamic organelles. Through a large-scale in vivo RNA interference (RNAi) screen that covered around a quarter of the Drosophila melanogaster genes (4000 genes), we identified 578 genes whose knockdown led to aberrant shapes or distributions of mitochondria. The complex analysis revealed that knockdown of the subunits of proteasomes, spliceosomes, and the electron transport chain complexes could severely affect mitochondrial morphology. The loss of Dhpr, a gene encoding an enzyme catalyzing tetrahydrobiopterin regeneration, leads to a reduction in the numbers of tyrosine hydroxylase neurons, shorter lifespan, and gradual loss of muscle integrity and climbing ability. The affected mitochondria in Dhpr mutants are swollen and have fewer cristae, probably due to lower levels of Drp1 S-nitrosylation. Overexpression of Drp1, but not of S-nitrosylation–defective Drp1, rescued Dhpr RNAi-induced mitochondrial defects. We propose that Dhpr regulates mitochondrial morphology and tissue homeostasis by modulating S-nitrosylation of Drp1.

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