期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 42, 页码 29235-29246出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.602938
关键词
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资金
- University of Padova (Progetto Strategico di Ateneo: Models of Mitochondrial Diseases)
- Fondazione CARIPLO: Scientific Research in Biomedicine (MITGEN: Definition and Characterization of Disease Genes in Mitochondrial Disorders)
- Telethon Project (MitMed: a Multicenter Consortium for the Identification and Characterization of Nuclear Genes Responsible for Human Mitochondrial Disorders) [GGP11011]
- Medical Research Council [MC_UP_1002/1] Funding Source: researchfish
- MRC [MC_UP_1002/1] Funding Source: UKRI
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 LSSurf1 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.
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