Subcomplex Ilambda specifically controls integrated mitochondrial functions in Caenorhabditis elegans.
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.
Falk
Marni J
MJ
Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA. falkm@email.chop.edu
Rosenjack
Julie R
JR
Polyak
Erzsebet
E
Suthammarak
Wichit
W
Chen
Zhongxue
Z
Morgan
Phil G
PG
Sedensky
Margaret M
MM
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
D042967:Electron Transport Complex I