Nuclear gene mutations as the cause of mitochondrial complex III deficiency

Fernández-Vizarra, Erika; Zeviani, Massimo

doi:10.3389/fgene.2015.00134

Cited by 124 publications

(126 citation statements)

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“…These findings have not been seen in other BCS1L associated pathologies [4], and stress that novel mutations in mitochondrial genes can produce different phenotypes.…”

Section: Discussionmentioning

confidence: 66%

Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model

Tegelberg

Tomašić

Kallijärvi

et al. 2017

Orphanet J Rare Dis

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BackgroundMitochondrial diseases due to defective respiratory chain complex III (CIII) are relatively uncommon. The assembly of the eleven-subunit CIII is completed by the insertion of the Rieske iron-sulfur protein, a process for which BCS1L protein is indispensable. Mutations in the BCS1L gene constitute the most common diagnosed cause of CIII deficiency, and the phenotypic spectrum arising from mutations in this gene is wide.ResultsA case of CIII deficiency was investigated in depth to assess respiratory chain function and assembly, and brain, skeletal muscle and liver histology. Exome sequencing was performed to search for the causative mutation(s). The patient’s platelets and muscle mitochondria showed respiration defects and defective assembly of CIII was detected in fibroblast mitochondria. The patient was compound heterozygous for two novel mutations in BCS1L, c.306A > T and c.399delA. In the cerebral cortex a specific pattern of astrogliosis and widespread loss of microglia was observed. Further analysis showed loss of Kupffer cells in the liver. These changes were not found in infants suffering from GRACILE syndrome, the most severe BCS1L-related disorder causing early postnatal mortality, but were partially corroborated in a knock-in mouse model of BCS1L deficiency.ConclusionsWe describe two novel compound heterozygous mutations in BCS1L causing CIII deficiency. The pathogenicity of one of the mutations was unexpected and points to the importance of combining next generation sequencing with a biochemical approach when investigating these patients. We further show novel manifestations in brain, skeletal muscle and liver, including abnormality in specialized resident macrophages (microglia and Kupffer cells). These novel phenotypes forward our understanding of CIII deficiencies caused by BCS1L mutations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0624-2) contains supplementary material, which is available to authorized users.

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“…These findings have not been seen in other BCS1L associated pathologies [4], and stress that novel mutations in mitochondrial genes can produce different phenotypes.…”

Section: Discussionmentioning

confidence: 66%

Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model

Tegelberg

Tomašić

Kallijärvi

et al. 2017

Orphanet J Rare Dis

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show abstract

“…For example, 45–60% of biochemically-validated cases of CI (Calvo et al, 2010; Haack et al, 2011), CII (Jain-Ghai et al, 2013), and CIII deficiency (Fernandez-Vizarra and Zeviani, 2015) lack molecular diagnoses. As such, we prioritized MXPs that interacted with respiratory chain components for functional investigations.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function

et al. 2016

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SUMMARY Mitochondria are essential for numerous cellular processes, yet hundreds of their proteins lack robust functional annotation. To reveal new functions for these proteins (termed MXPs) we assessed condition-specific protein-protein interactions for 50 select MXPs using affinity enrichment mass spectrometry. Our data connect MXPs to diverse mitochondrial processes, including multiple aspects of respiratory chain function. Building upon these observations, we validated C17orf89 as a complex I (CI) assembly factor. Disruption of C17orf89 markedly reduced CI activity, and its depletion is found in an unresolved case of CI deficiency. We likewise discovered that LYRM5 interacts with and deflavinates the electron transferring flavoprotein that shuttles electrons to coenzyme Q (CoQ). Finally, we identified a dynamic human CoQ biosynthetic complex involving multiple MXPs whose topology we map using purified components. Collectively, our data lend new mechanistic insight into respiratory chain-related activities and prioritize hundreds of additional interactions for further exploration of mitochondrial protein function.

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“…In the reported CIII assembly models, incorporation of CORE2 allows the formation of a non-functional intermediate called pre-CIII, which contains CORE2 and the rest of CIII subunits except RISP and the smallest subunit (Qcr10 in yeast, UQCR11 in mammals), which are incorporated at a later assembly stage (Fernandez-Vizarra and Zeviani, 2015; Smith et al, 2012). This late assembly step is promoted by LYRM7/MZM1L, an assembly factor that binds RISP to stabilize it prior to its incorporation into CIII.…”

Section: Resultsmentioning

confidence: 99%

COX7A2L Is a Mitochondrial Complex III Binding Protein that Stabilizes the III2+IV Supercomplex without Affecting Respirasome Formation

et al. 2016

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Summary Mitochondrial respiratory chain (MRC) complexes I, III and IV associate into a variety of supramolecular structures known as supercomplexes and respirasomes. While COX7A2L was originally described as a supercomplex-specific factor responsible for the dynamic association of complex IV into these structures to adapt MRC function to metabolic variations, this role has been disputed. Here we further examine the functional significance of COX7A2L in the structural organization of the mammalian respiratory chain. As in the mouse, human COX7A2L binds primarily to free mitochondrial complex III and to a minor extent to complex IV to specifically promote the stabilization of the III2+IV supercomplex without affecting respirasome formation. Furthermore, COX7A2L does not affect the biogenesis, stabilization and function of the individual OXPHOS complexes. These data show that independent regulatory mechanisms for the biogenesis and turnover of different MRC supercomplex structures co-exist.

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Nuclear gene mutations as the cause of mitochondrial complex III deficiency

Cited by 124 publications

References 83 publications

Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model

Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model

Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function

COX7A2L Is a Mitochondrial Complex III Binding Protein that Stabilizes the III2+IV Supercomplex without Affecting Respirasome Formation

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