کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2184889 1095945 2011 14 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Mutations in the Gene Encoding C8orf38 Block Complex I Assembly by Inhibiting Production of the Mitochondria-Encoded Subunit ND1
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیولوژی سلول
پیش نمایش صفحه اول مقاله
Mutations in the Gene Encoding C8orf38 Block Complex I Assembly by Inhibiting Production of the Mitochondria-Encoded Subunit ND1
چکیده انگلیسی

The assembly of complex I (NADH–ubiquinone oxidoreductase) is a complicated process, requiring the integration of 45 subunits encoded by both nuclear and mitochondrial DNAs into a structure of approximately 1 MDa. A number of “assembly factors” that aid complex I biogenesis have recently been described, including C8orf38. This protein was identified as an assembly factor by its evolutionary conservation in organisms containing complex I and by a C8orf38 mutation in a patient presenting with Leigh syndrome and isolated complex I deficiency. In this report, we have undertaken the characterization of C8orf38 and its role in complex I assembly. Analysis of mitochondria from fibroblasts of a patient harboring a C8orf38 mutation showed almost undetectable levels of steady-state complex I and defective biogenesis of the mtDNA-encoded subunit ND1. Complementation with wild-type C8orf38 restored the levels of both ND1 and complex I, confirming the C8orf38 mutation as the cause of the complex I defect in the patient. In the absence of ND1 in patient cells, early- and mid-stage intermediate complexes were still formed; however, assembly of late-stage intermediates was impaired, indicating a convergence point in the assembly process. While C8orf38 appears to behave at a step in complex I biogenesis similar to that of the assembly factor C20orf7, complementation studies showed that both proteins are required for ND1 synthesis/stabilization. We conclude that C8orf38 is a crucial factor required for the translation and/or integration of ND1 into an early-stage assembly intermediate and that mutation of C8orf38 disrupts the initial stages of complex I biogenesis.

Graphical AbstractFigure optionsDownload high-quality image (143 K)Download as PowerPoint slideResearch Highlights
► C8orf38 is a mitochondrial protein involved in complex I biogenesis.
► Mutations in C8orf38 result in Leigh disease with isolated complex I deficiency.
► C8orf38 is involved in the biogenesis of the complex I subunit ND1.
► Defects in C8orf38 disrupt the assembly of complex I.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular Biology - Volume 414, Issue 3, 2 December 2011, Pages 413–426
نویسندگان
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