title: Subcomplex Ilambda specifically controls integrated mitochondrial functions in Caenorhabditis elegans.
abstract: Complex I dysfunction is a common, heterogeneous cause of human mitochondrial disease having poorly understood pathogenesis. The extensive conservation of complex I composition between humans and Caenorhabditis elegans permits analysis of individual subunit contribution to mitochondrial functions at both the whole animal and mitochondrial levels. We provide the first experimentally-verified compilation of complex I composition in C. elegans, demonstrating 84% conservation with human complex I. Individual subunit contribution to mitochondrial respiratory capacity, holocomplex I assembly, and animal anesthetic behavior was studied in C. elegans by RNA interference-generated knockdown of nuclear genes encoding 28 complex I structural subunits and 2 assembly factors. Not all complex I subunits directly impact respiratory capacity. Subcomplex Ilambda subunits along the electron transfer pathway specifically control whole animal anesthetic sensitivity and complex II upregulation, proportionate to their relative impairment of complex I-dependent oxidative capacity. Translational analysis of complex I dysfunction facilitates mechanistic understanding of individual gene contribution to mitochondrial disease. We demonstrate that functional consequences of complex I deficiency vary with the particular subunit that is defective.
authors: Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA. falkm@email.chop.edu
authors: Marni J
authors: MJ
authors: Falk
authors: Julie R
authors: JR
authors: Rosenjack
authors: Erzsebet
authors: E
authors: Polyak
authors: Wichit
authors: W
authors: Suthammarak
authors: Zhongxue
authors: Z
authors: Chen
authors: Phil G
authors: PG
authors: Morgan
authors: Margaret M
authors: MM
authors: Sedensky
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D055785:Gene Knockdown Techniques; D013058:Mass Spectrometry; D008928:Mitochondria / Q000502:physiology*; D010085:Oxidative Phosphorylation; D011048:Polarography; D016133:Polymerase Chain Reaction; D034622:RNA Interference
chemical_list: D042967:Electron Transport Complex I