Leigh syndrome in Drosophila melanogaster: morphological and biochemical characterization of Surf1 post-transcriptional silencing.

TitleLeigh syndrome in Drosophila melanogaster: morphological and biochemical characterization of Surf1 post-transcriptional silencing.
Publication TypeJournal Article
Year of Publication2014
AuthorsDa-Rè, C, von Stockum, S, Biscontin, A, Millino, C, Cisotto, P, Zordan, MA, Zeviani, M, Bernardi, P, De Pittà, C, Costa, R
JournalJ Biol Chem
Date Published2014 Oct 17
KeywordsAnimals, ATP Synthetase Complexes, Cell Line, Drosophila melanogaster, Drosophila Proteins, Electron Transport, Electron Transport Complex IV, Gene Expression Profiling, Gene Silencing, Humans, Leigh Disease, Membrane Potential, Mitochondrial, Membrane Proteins, Mifepristone, Mitochondria, Mitochondrial Proteins, Mutation, Oxygen, RNA Interference, RNA Processing, Post-Transcriptional, RNA, Double-Stranded, Transcription, Genetic

Leigh Syndrome (LS) is the most common early-onset, progressive mitochondrial encephalopathy usually leading to early death. The single most prevalent cause of LS is occurrence of mutations in the SURF1 gene, and LS(Surf1) patients show a ubiquitous and specific decrease in the activity of mitochondrial respiratory chain complex IV (cytochrome c oxidase, COX). SURF1 encodes an inner membrane mitochondrial protein involved in COX assembly. We established a Drosophila melanogaster model of LS based on the post-transcriptional silencing of CG9943, the Drosophila homolog of SURF1. Knockdown of Surf1 was induced ubiquitously in larvae and adults, which led to lethality; in the mesodermal derivatives, which led to pupal lethality; or in the central nervous system, which allowed survival. A biochemical characterization was carried out in knockdown individuals, which revealed that larvae unexpectedly displayed defects in all complexes of the mitochondrial respiratory chain and in the F-ATP synthase, while adults had a COX-selective impairment. Silencing of Surf1 expression in Drosophila S2R(+) cells led to selective loss of COX activity associated with decreased oxygen consumption and respiratory reserve. We conclude that Surf1 is essential for COX activity and mitochondrial function in D. melanogaster, thus providing a new tool that may help clarify the pathogenic mechanisms of LS.

Alternate JournalJ. Biol. Chem.
Citation Key10.1074/jbc.M114.602938
PubMed ID25164807
PubMed Central IDPMC4200275
Grant ListGGP11011 / / Telethon / Italy
MC_UP_1002/1 / / Medical Research Council / United Kingdom