Human achondroplasia: defective mitochondrial oxidative energy metabolism may produce the pathophysiology.
A summary is presented of previous studies by other investigators of human achondroplasia and dyschondroplastic animal models. In addition, studies previously reported from our laboratories are discussed, and they demonstrate that defective oxidative energy metabolism is present in mitochondrial preparations from achondroplastic human subjects and rabbits (ac/ac) with chondrodystrophy. The results of the studies support the hypothesis discussed fully in the manuscript that a partial defect in mitochondrial oxidative metabolism in achondroplastic subjects is expressed specifically in the growth plates of the long bones because this tissue has the lowest oxygen tension of any bodily organ undergoing active proliferation, thus leading to the achondroplastic phenotype in humans and the ac/ac rabbit. In the ac/ac rabbit phosphorylation at the cytochrome c oxidase region (site III) of the terminal respiratory system was shown to be absent in mitochondrial preparations from the livers of newborn ac/ac rabbits. Normal-appearing littermates did not exhibit the defect. Studies of mitochondrial preparations from human skin fibroblasts (grown in tissue culture) from normal human subjects and subjects with homozygous achondroplasia demonstrated that concentrations of cytochrome a3 were decreased approximately 80% in preparations from homozygous achondroplastic cells. Levels of cytochrome a3 in heterozygous achondroplastic cells were intermediate between the levels in normal cells and homozygous achondroplastic cells demonstrating the effects of gene dosage. Determination of total heme a (as the pyridine hemochromogen) in the normal and achondroplastic preparations from human subjects showed that the observed decrease in concentration of cytochrome a3 in the achondroplastic preparations was due to an absence of cytochrome a3 and not to a change in its absorbancy (extinction coefficient).
Mackler
B
B
Department of Pediatrics, University of Washington, Seattle 98195.
Shepard
T H
TH
D000130:Achondroplasia / Q000209:etiology*; D000818:Animals; D003580:Cytochromes / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D004951:Esterification; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010009:Osteochondrodysplasias / Q000209:etiology; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D010766:Phosphorylation; D011817:Rabbits
D003580:Cytochromes; D003576:Electron Transport Complex IV; D010100:Oxygen