Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy.
We investigated two unrelated children with an isolated defect of mitochondrial complex III activity. The clinical picture was characterized by a progressive encephalopathy featuring early-onset developmental delay, spasticity, seizures, lactic acidosis, brain atrophy and MRI signal changes in the basal ganglia. Both children were compound heterozygotes for novel mutations in the human bc1 synthesis like (BCS1L) gene, which encodes an AAA mitochondrial protein putatively involved in both iron homeostasis and complex III assembly. The pathogenic role of the mutations was confirmed by complementation assays, using a DeltaBcs1 strain of Saccharomyces cerevisiae. By investigating complex III assembly and the structural features of the BCS1L gene product in skeletal muscle, cultured fibroblasts and lymphoblastoid cell lines from our patients, we have demonstrated, for the first time in a mammalian system, that a major function of BCS1L is to promote the maturation of complex III and, more specifically, the incorporation of the Rieske iron-sulfur protein into the nascent complex. Defective BCS1L leads to the formation of a catalytically inactive, structurally unstable complex III. We have also shown that BCS1L is contained within a high-molecular-weight supramolecular complex which is clearly distinct from complex III intermediates.
Fernandez-Vizarra
Erika
E
Department of Molecular Neurogenetics, , Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
Bugiani
Marianna
M
Goffrini
Paola
P
Carrara
Franco
F
Farina
Laura
L
Procopio
Elena
E
Donati
Alice
A
Uziel
Graziella
G
Ferrero
Iliana
I
Zeviani
Massimo
M
D000074183:ATPases Associated with Diverse Cellular Activities; D000595:Amino Acid Sequence; D001483:Base Sequence; D001921:Brain / Q000473:pathology; D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002675:Child, Preschool; D018076:DNA, Complementary / Q000235:genetics; D014450:Electron Transport Complex III / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005816:Genetic Complementation Test; D006579:Heterozygote; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000737:chemistry / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
C435491:BCS1L protein, human; D018076:DNA, Complementary; D007506:Iron-Sulfur Proteins; D046912:Multiprotein Complexes; D011994:Recombinant Proteins; C037989:Rieske iron-sulfur protein; D000074183:ATPases Associated with Diverse Cellular Activities; D014450:Electron Transport Complex III