title: Leigh syndrome in Drosophila melanogaster: morphological and biochemical characterization of Surf1 post-transcriptional silencing.
abstract: 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.
authors.affiliation: From the Departments of Biology and.
authors.forename: Caterina
authors.initials: C
authors.lastname: Da-Rè
authors.affiliation: Biomedical Sciences and.
authors.forename: Sophia
authors.initials: S
authors.lastname: von Stockum
authors.affiliation: From the Departments of Biology and.
authors.forename: Alberto
authors.initials: A
authors.lastname: Biscontin
authors.affiliation: CRIBI Biotechnology Centre, University of Padova, 35121 Padova, Italy and.
authors.forename: Caterina
authors.initials: C
authors.lastname: Millino
authors.affiliation: From the Departments of Biology and.
authors.forename: Paola
authors.initials: P
authors.lastname: Cisotto
authors.affiliation: From the Departments of Biology and.
authors.forename: Mauro A
authors.initials: MA
authors.lastname: Zordan
authors.affiliation: MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.affiliation: Biomedical Sciences and.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.affiliation: From the Departments of Biology and cristiano.depitta@unipd.it.
authors.forename: Cristiano
authors.initials: C
authors.lastname: De Pittà
authors.affiliation: From the Departments of Biology and rodolfo.costa@unipd.it.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Costa
mesh_terms: D025181:ATP Synthetase Complexes / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics* / Q000502:physiology; D004331:Drosophila melanogaster / Q000378:metabolism*; D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000378:metabolism; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006801:Humans; D007888:Leigh Disease / Q000235:genetics*; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D015735:Mifepristone / Q000737:chemistry; D008928:Mitochondria / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D012330:RNA, Double-Stranded / Q000737:chemistry; D014158:Transcription, Genetic
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D012330:RNA, Double-Stranded; C092928:Surf-1 protein; C000593793:Surf1 protein, Drosophila; D015735:Mifepristone; D003576:Electron Transport Complex IV; D025181:ATP Synthetase Complexes; D010100:Oxygen
keywords: Cytochrome c; Cytochrome c oxidase (Complex IV); Drosophila; Mitochondria; Mitochondrial Disease; Mitochondrial Respiratory Chain Complex