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

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.

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

“…During the writing of the manuscript, Wanschers and colleagues proposed that C11orf83, which they renamed UQCC3, would be the human ortholog of Cbp4p. They identified a missense mutation in C11orf83 (Val20Glu) that resulted in the destabilization of the protein in a patient and caused a bc 1 complex deficiency (91). In addition to these findings, we have demonstrated that C11orf83 interacts with the bc 1 complex.…”

“…We also demonstrated that C11orf83 is involved in the SC stabilization and binds to CL, two important features which had never been studied in yeast. Importantly, Wanschers and colleagues reported that cbp4⌬ mutant yeast strains could not be complemented by C11orf83 (91). This result could be due to a low level of sequence similarity between Cbp4p and C11orf83.…”

Mitochondrial C11orf83 is a potent Antiviral Protein Independent of interferon production

“…C11orf83 is currently known as an assembly factor of Complex III of the electron transport chain and is required for proper mitochondrial morphology and function. C11orf83-deficient cells displayed complex III assembly deficiency and abnormal mitochondria with an impaired oxidative phosphorylation3031. In the present study, we found that C11orf83 also is sensitive to viral infection, which was rapidly upregulated when cells were infected by VSV.…”

“…Patient cells with a homozygous c.59T > A missense mutation in C11orf83 have reduced complex III activity. The patient displays lactic acidosis, hypoglycemia, hypotonia, delayed development and severely delayed psychomotor development31. In the present study, we reported the identification of C11orf83 as a novel antiviral protein.…”

Management of Leigh syndrome: Current status and new insights

“…Early identification of CoQ10 deficiency may be clinically meaningful as some patients with LS and CoQ10 deficiency respond to supplementation . Nuclear mutations for complex III (CIII) deficiency include BCS1L , TTC19 , CYC1 , UQCC2, 3 , LYRM7 and UQCRQ . Mutations in TTC19 are usually nonsense whereas in BCS1L they are missense although either can lead to a range of neurological symptoms.…”