title: Deficiency of pyruvate dehydrogenase complex (PDHC) in Leigh's disease fibroblasts: an abnormality in lipoamide dehydrogenase affecting PDHC activation.
abstract: Several groups have reported abnormalities of the pyruvate dehydrogenase complex (PDHC) in cultured cells or other tissues from patients with Leigh's disease (subacute necrotizing encephalomyelopathy). We therefore undertook studies to elucidate the molecular basis of the defect of PDHC in cultured skin fibroblasts from two patients with Leigh's disease. The deficit of total PDHC activity in homogenates of Leigh's disease fibroblasts could be restored by adding exogenous lipoamide dehydrogenase (LAD, E3), the third component of PDHC. The LAD in these Leigh's disease cells had a markedly reduced ability (less than 20% of normal LAD) to reconstitute with other PDHC components to form active enzyme complex. A polyclonal antibody to pig heart LAD inhibited LAD activity in control cells more efficiently than in Leigh's disease cells. Other mitochondrial enzyme activities and growth of these two Leigh's disease cells appeared normal. These results suggest that the deficiency of PDHC in these two patients with Leigh's disease was due to a structural abnormality of the LAD component of PDHC.
authors.affiliation: Department of Neurology, Cornell University Medical College, Burke Rehabilitation Center, White Plains, NY.
authors.forename: L M
authors.initials: LM
authors.lastname: Hinman
authors.forename: K F
authors.initials: KF
authors.lastname: Sheu
authors.forename: A C
authors.initials: AC
authors.lastname: Baker
authors.forename: Y T
authors.initials: YT
authors.lastname: Kim
authors.forename: J P
authors.initials: JP
authors.lastname: Blass
mesh_terms: D001928:Brain Diseases, Metabolic / Q000150:complications*; D008058:Dihydrolipoamide Dehydrogenase / Q000378:metabolism*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D007888:Leigh Disease / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D008928:Mitochondria / Q000201:enzymology; D011768:Pyruvate Dehydrogenase Complex / Q000096:biosynthesis / Q000378:metabolism*; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000150:complications*; D015323:Pyruvate Metabolism, Inborn Errors / Q000150:complications*; D012867:Skin / Q000201:enzymology* / Q000473:pathology
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D008058:Dihydrolipoamide Dehydrogenase