A mutation in the human CBP4 ortholog UQCC3 impairs complex III assembly, activity and cytochrome b stability

Hum Mol Genet. 2014 Dec 1;23(23):6356-65. doi: 10.1093/hmg/ddu357.

Bas F J Wanschers ¹, Radek Szklarczyk ², Mariël A M van den Brand ³, An Jonckheere ³, Janneke Suijskens ⁴, Roel Smeets ⁴, Richard J Rodenburg ³, Katharina Stephan ⁵, Ingrid B Helland ⁶, Areej Elkamil ⁷, Terje Rootwelt ⁸, Martin Ott ⁵, Lambert van den Heuvel ⁹, Leo G Nijtmans ³, Martijn A Huynen ¹⁰

Affiliations

1 Centre for Molecular and Biomolecular Informatics, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands, Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands.
2 Centre for Molecular and Biomolecular Informatics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands, Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, 6200MD Maastricht, The Netherlands.
3 Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands.
4 Laboratory of Genetic, Endocrine, and Metabolic Diseases, Department of Laboratory Medicine, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen,The Netherlands.
5 Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius väg 16C, Stockholm SE-106 91, Sweden.
6 Department of Pediatrics, Oslo University Hospital, 0424 Oslo, Norway.
7 Department of Pediatrics, St Olav's University Hospital, Trondheim 7006, Norway.
8 Department of Pediatrics, Oslo University Hospital, 0424 Oslo, Norway, University of Oslo, Oslo 0424, Norway and.
9 Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands, Laboratory of Genetic, Endocrine, and Metabolic Diseases, Department of Laboratory Medicine, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen,The Netherlands, Department of Pediatrics, Catholic University Leuven, Leuven 3000, Belgium.
10 Centre for Molecular and Biomolecular Informatics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands, [email protected].

PMID: 25008109 DOI: 10.1093/hmg/ddu357

Abstract

Complex III (cytochrome bc1) is a protein complex of the mitochondrial inner membrane that transfers electrons from ubiquinol to cytochrome c. Its assembly requires the coordinated expression of mitochondrial-encoded cytochrome b and nuclear-encoded subunits and assembly factors. Complex III deficiency is a severe multisystem disorder caused by mutations in subunit genes or assembly factors. Sequence-profile-based orthology predicts C11orf83, hereafter named UQCC3, to be the ortholog of the Fungal complex III assembly factor CBP4. We describe a homozygous c.59T>A missense mutation in UQCC3 from a consanguineous patient diagnosed with isolated complex III deficiency, displaying lactic acidosis, hypoglycemia, hypotonia and delayed development without dysmorphic features. Patient fibroblasts have reduced complex III activity and lower levels of the holocomplex and its subunits than controls. They have no detectable UQCC3 protein and have lower levels of cytochrome b protein. Furthermore, in patient cells, cytochrome b is absent from a high-molecular-weight complex III. UQCC3 is reduced in cells depleted for the complex III assembly factors UQCC1 and UQCC2. Conversely, absence of UQCC3 in patient cells does not affect UQCC1 and UQCC2. This suggests that UQCC3 functions in the complex III assembly pathway downstream of UQCC1 and UQCC2 and is consistent with what is known about the function of Cbp4 and of the Fungal orthologs of UQCC1 and UQCC2, Cbp3 and Cbp6. We conclude that UQCC3 functions in complex III assembly and that the c.59T>A mutation has a causal role in complex III deficiency.

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