Cellular pathophysiological consequences of BCS1L mutations in mitochondrial complex III enzyme deficiency

Abstract

Mutations in BCS1L, an assembly factor that facilitates the insertion of the catalytic Rieske Iron‐Sulfur subunit into respiratory chain complex III, result in a wide variety of clinical phenotypes that range from the relatively mild Björnstad syndrome to the severe GRACILE syndrome. To better understand the pathophysiological consequences of such mutations, we studied fibroblasts from six complex III‐deficient patients harboring mutations in the BCS1L gene. Cells from patients with the most severe clinical phenotypes exhibited slow growth rates in glucose medium, variable combined enzyme deficiencies, and assembly defects of respiratory chain complexes I, III, and IV, increased H2O2 levels, unbalanced expression of the cellular antioxidant defenses, and apoptotic cell death. In addition, all patients showed cytosolic accumulation of the BCS1L protein, suggestive of an impaired mitochondrial import, assembly or stability defects of the BCS1L complex, fragmentation of the mitochondrial networks, and decreased MFN2 protein levels. The observed structural alterations were independent of the respiratory chain function and ROS production. Our results provide new insights into the role of pathogenic BCS1L mutations in mitochondrial function and dynamics. Hum Mutat 31:–12, 2010. © 2010 Wiley‐Liss, Inc.

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…A similar assembly phenotype has been recently described in a NDUFS4 knock-out mice (Calvaruso et al, 2011). The same argument would serve to explain why failures in the insertion of the complex III subunits cytochrome b or RISP may lead to combined complex I and complex III deficiencies in human tissues (Lamantea et al, 2002;Acín-Perez et al, 2004;Fernandez-Vizarra et al, 2007;Moran et al, 2010a). However exceptions exist and, contrary to what is commonly accepted, there is no such a clear correlation between the severity of the assembly impairments of RC complexes III and IV, and the supposed pleiotropic complex I assembly and activity defects.…”

“…For this reason structural alterations that severely impair the biosynthesis of complexes III and IV may induce pleiotropic deleterious effects on the assembly and enzyme activity of complex I that will be probably translated into combined respiratory deficiencies of two or more RC complexes. Accordingly, pathogenic mutations in the cytochrome b (CYTB) or BCS1L genes that severely affect complex III assembly, may lead to pleiotropic activity defects of other RC complexes in patients´ tissues (Lamantea et al, 2002;Fernandez-Vizarra et al, 2007;Moran et al, 2010a). Similarly, mutations in the COX1 gene that hamper complex IV assembly may cause combined enzyme deficiencies of complexes I and IV (D'Aurelio et al, 2006); and conversely, mutations affecting complex I subunits or assembly factors have been described in patients´ tissues with combined deficiencies of RC complexes I and III (Budde et al, 2000;Ugalde et al, 2004), or I and IV (Saada et al, 2011).…”

“…Regarding complex III enzyme deficiency, two studies analyzed the impact on ROS production of mutations in the BCS1L assembly factor, involved in the insertion of the catalytic Rieske Iron Sulphur Protein (RISP) into complex III (Cruciat et al, 1999;Hinson et al, 2007;Moran et al, 2010a). One of these studies revealed defective complex III enzyme activities and respirasome assembly defects that correlated with increased superoxide levels in isolated mitochondria of lymphocytes from patients with either complex III deficiency or Björnstad syndrome (Hinson et al, 2007).…”

“…One of these studies revealed defective complex III enzyme activities and respirasome assembly defects that correlated with increased superoxide levels in isolated mitochondria of lymphocytes from patients with either complex III deficiency or Björnstad syndrome (Hinson et al, 2007). The second study was performed with skin fibroblasts from six complex III-deficient patients with BCS1L mutations, which showed a marked correlation between the severity of the enzyme deficiencies and assembly defects of the RC complexes I, III and IV and raised H 2 O 2 levels, together with an unbalanced expression of the cellular antioxidant defenses (Moran et al, 2010a). Accordingly, complexes I, III, IV and supercomplexes were decreased in RISP-deficient mouse cells that displayed high superoxide levels (Diaz et al, 2011).…”

“…Mitochondrial network fragmentation has been mainly described in complex I and complex III-deficient cells (Pham et al, 2004;Benard et al, 2007;Koopman et al, 2007;Moran et al, 2010a).…”