Characterization of complex III deficiency and liver dysfunction in GRACILE syndrome caused by a BCS1L mutation

Kotarsky, Heike; Karikoski, Riitta; Mörgelin, Matthias; Marjavaara, Sanna; Bergman, Petra; Zhang, De-Liang; Smet, Joél; Coster, Rudy Van; Fellman, Vineta

doi:10.1016/j.mito.2010.05.009

Cited by 37 publications

(38 citation statements)

References 66 publications

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“…This mutation causes severe symptoms such as growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis and early death. Complex III deficiency was detected in the livers of GRACILE patients which could be explained by lower RISP levels as a result of dysfunctional BCS1L protein (Kotarsky et al, 2010). RISP in these patients may be more susceptible to proteases since it was shown that in the presence of dysfunctional Bcs1, Rip1 is present as unassembled monomers (Cruciat et al, 1999).…”

Section: Gracile Syndromementioning

confidence: 99%

Bcs1, a AAA protein of the mitochondria with a role in the biogenesis of the respiratory chain

Wagener

Neupert

2012

Journal of Structural Biology

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Section: Gracile Syndromementioning

confidence: 99%

Bcs1, a AAA protein of the mitochondria with a role in the biogenesis of the respiratory chain

Wagener

Neupert

2012

Journal of Structural Biology

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“…Whereas 13 bc 1 complex assembly factors were identified in yeast, only 5 are currently characterized in mammals: BCS1L (8), TTC19 (9), UQCC1 and UQCC2 (10), and LYRM7 (11). Deleterious mutations in the BCS1L (12) and TTC19 (9) genes were reported to cause GRACILE (growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and early death) syndrome and neurological impairments, respectively, due to a defective bc 1 complex assembly.…”

mentioning

confidence: 99%

C11orf83, a Mitochondrial Cardiolipin-Binding Protein Involved in bc₁ Complex Assembly and Supercomplex Stabilization

Desmurs

Foti

Raemy

et al. 2015

Molecular and Cellular Biology

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e Mammalian mitochondria may contain up to 1,500 different proteins, and many of them have neither been confidently identified nor characterized. In this study, we demonstrated that C11orf83, which was lacking experimental characterization, is a mitochondrial inner membrane protein facing the intermembrane space. This protein is specifically associated with the bc 1 complex of the electron transport chain and involved in the early stages of its assembly by stabilizing the bc 1 core complex. C11orf83 displays some overlapping functions with Cbp4p, a yeast bc 1 complex assembly factor. Therefore, we suggest that C11orf83, now called UQCC3, is the functional human equivalent of Cbp4p. In addition, C11orf83 depletion in HeLa cells caused abnormal crista morphology, higher sensitivity to apoptosis, a decreased ATP level due to impaired respiration and subtle, but significant, changes in cardiolipin composition. We showed that C11orf83 binds to cardiolipin by its ␣-helices 2 and 3 and is involved in the stabilization of bc 1 complex-containing supercomplexes, especially the III 2 /IV supercomplex. We also demonstrated that the OMA1 metalloprotease cleaves C11orf83 in response to mitochondrial depolarization, suggesting a role in the selection of cells with damaged mitochondria for their subsequent elimination by apoptosis, as previously described for OPA1. Mitochondria are membrane-enclosed organelles composed of several compartments which perform specialized and interconnected functions such as oxidative phosphorylation (OXPHOS), cell death, or carbohydrate and fatty acid metabolisms. OXPHOS, which provides most of the ATP used by the cell, takes place in the inner membrane (IM) and involves five complexes. Redox reactions are carried out by complex I (NADH: ubiquinone oxidoreductase; EC 1.6.5.3), complex II (succinate: ubiquinone oxidoreductase; EC 1.3.5.1), complex III (ubiquinol: ferricytochrome c oxidoreductase; EC 1.10.2.2), and complex IV (cytochrome c oxidoreductase; EC 1.9.3.1). Then, the ATP synthase, complex V (F 1 F 0 ATPase; EC 3.6.3.14), uses the energy released by respiration for ATP generation. The assembly of the OXPHOS complexes requires additional nuclear proteins called assembly factors (1). The physiological importance of these assembly factors is proven by the number of human diseases associated with mutations in genes encoding them (1).Complex III, also called cytochrome bc 1 complex, is a central component of the electron transport chain (ETC). It transfers electrons from coenzyme Q reduced either by complex I through NADH-linked substrates or by complex II through reduced flavin adenine dinucleotide (FADH 2 )-linked substrates to cytochrome c. The mammalian bc 1 complex, which forms as a stable dimer (2), is composed of 11 subunits, among which only MT-CYB is encoded by the mitochondrial genome (3, 4). Most of the work on the bc 1 complex assembly has been performed with Saccharomyces cerevisiae and has shown this to be a multistep process involving several subcomplexes and assembly factors (5...

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“…This was clearly illustrated in patients with mutations in the BCS1L assembly gene. The catalytic activity of complex III in these patients was only slightly decreased (Fellman 2002;De Meirleir et al 2003) although BN-PAGE gel electrophoresis clearly demonstrated a decreased amount of protein in the complex (Kotarsky et al 2010).…”

Section: Introductionmentioning

confidence: 73%

Complex III staining in blue native polyacrylamide gels

Smet

Paepe

Seneca

et al. 2011

J of Inher Metab Disea

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For more than a decade now blue native polyacrylamide gel electrophoresis (BN-PAGE) has been used for the study of the oxidative phosphorylation (OXPHOS) complexes. Catalytic activities of complexes I, II, IV and V can be assessed, after separation by gel electrophoresis, by incubation of the BN-PAGE gel in specific staining solutions. However, until now, a reliable staining method for testing ubiquinol cytochrome c oxidoreductase (complex III) activity by BN-PAGE gel techniques was not available. In addition, spectrophotometric methods currently in use for detection of complex III deficiency in patients are not very sensitive. Here, we describe a newly developed diagnostic method for visualization of complex III activity by direct in-gel evaluation of ubiquinol cytochrome oxidoreductase activity. We validated the method by reporting the results in six patients with previously characterised complex III defects.

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Characterization of complex III deficiency and liver dysfunction in GRACILE syndrome caused by a BCS1L mutation

Cited by 37 publications

References 66 publications

Bcs1, a AAA protein of the mitochondria with a role in the biogenesis of the respiratory chain

Bcs1, a AAA protein of the mitochondria with a role in the biogenesis of the respiratory chain

C11orf83, a Mitochondrial Cardiolipin-Binding Protein Involved in bc₁ Complex Assembly and Supercomplex Stabilization

Complex III staining in blue native polyacrylamide gels

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Characterization of complex III deficiency and liver dysfunction in GRACILE syndrome caused by a BCS1L mutation

Cited by 37 publications

References 66 publications

Bcs1, a AAA protein of the mitochondria with a role in the biogenesis of the respiratory chain

Bcs1, a AAA protein of the mitochondria with a role in the biogenesis of the respiratory chain

C11orf83, a Mitochondrial Cardiolipin-Binding Protein Involved in bc1 Complex Assembly and Supercomplex Stabilization

Complex III staining in blue native polyacrylamide gels

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C11orf83, a Mitochondrial Cardiolipin-Binding Protein Involved in bc₁ Complex Assembly and Supercomplex Stabilization