On Sept. 18, 2019, Science Advances Journal published a research article entitled “Large-scale RNAi screen identified Dhpr as a regulator of mitochondrial morphology and tissue homeostasis” by Zou et al from Dr. Chao Tong’s laboratory.
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 RNA interference (RNAi) screen that covered around a quarter of the Drosophila melanogaster genes (4000 genes), Zou et al. 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, spliceosomes, and the electron transport chain complexes could severely affect mitochondrial morphology.
In addition, they identified a gene Dhpr, encoding an enzyme required for regeneration of tetrahydrobiopterin, whose lost led to mitochondrial morphology defects. The affected mitochondria in Dhpr mutants were swollen and had less cristae. Further analysis revealed that the loss of Dhpr led to the reduction in the numbers of tyrosine hydroxylase neurons, shorter lifespan, and gradual loss of muscle integrity and climbing ability, phenotypes that were very similar to those observed when the Parkinson’s disease–related genes were lost. Mechanistically, they found that the enzyme activity of Dhpr was critical for the S-nitrosylation of the core mitochondrial fission machinery Drp1, which is essential for Drp1 activity.
This study not only serves as a rich source of information to study mitochondrial morphology but also sheds light on the molecular mechanisms underlying the diseases caused by the loss of Dhpr-related genes.
Dr. Jia Zhou is the leading author and Dr. Chao Tong is the corresponding author of this research article. This study was supported by the National Key Research & Developmental Program of China , the National Natural Science Foundation of China, the Natural Science Foundation of Zhejiang Province, the National Basic Research Program of China, and Fundamental Research Funds for the Central Universities.
The model of how Dhpr regulates mitochondrial morphology.
