HIGD2A is required for assembly of the COX3 module of human mitochondrial complex IV

Hock, Daniella H; Reljić, Boris; C, Ang; Mountford, Hayley S.; Compton, Alison G.; Ryan, Michael; Thorburn, David R.; Stroud, David A.

doi:10.1101/787721

Cited by 14 publications

(15 citation statements)

References 74 publications

(110 reference statements)

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“…A myriad of assembly factors is necessary for the synthesis, translocation, stabilization and incorporation of the metal groups in both MT-CO1 and MT-CO2 [187]. Other assembly factors such as PET100, PET117 and MR-1S work on the middle stages of assembly [186] and only one, HIGD2A, is known to promote the incorporation of the MT-CO3 module in the final steps of cIV assembly [188,189].…”

Section: Accepted Articlementioning

confidence: 99%

Mitochondrial disorders of the OXPHOS system

2020

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Mitochondrial disorders are amongst the most frequent inborn errors of metabolism, their primary cause being the dysfunction of the oxidative phosphorylation system (OXPHOS). OXPHOS is composed of the electron transport chain (ETC), formed by four multimeric enzymes and two mobile electron carriers, plus an ATP synthase (also called complex V). The ETC performs the redox reactions involved in cellular respiration while generating the proton motive force used by complex V to synthesize ATP. OXPHOS biogenesis involves multiple steps, starting from the expression of genes encoded in physically separated genomes, namely the mitochondrial and nuclear DNA, to the coordinated assembly of components and cofactors building each individual complex and eventually the supercomplexes. The genetic cause underlying around half of the diagnosed mitochondrial disease cases is currently known. Many of these cases result from pathogenic variants in genes encoding structural subunits or additional factors directly involved in the assembly of the ETC complexes. Here we review the historical and most recent findings concerning the clinical phenotypes and the molecular pathological mechanisms underlying this particular group of disorders.

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Section: Accepted Articlementioning

confidence: 99%

Mitochondrial disorders of the OXPHOS system

2020

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“…Mammalian complex IV consists of 14 subunits of which three are core subunits encoded on mtDNA, MT-CO1 (frequently referred to as COX1) , MT-CO2 ( COX2 ) and MT-CO3 ( COX3 ) with the remainder encoded by nDNA, COX4 (with 2 possible isoforms encoded on separate genes, COX4I1 and COX4I2 ), COX5A , COX5B , COX6A (2 possible isoforms, COX6A1 - 2 ), COX6B (2 isoforms, COX6B1 - 2 ), COX6C , COX7A (3 isoforms, COX7A1 - 3 ), COX7B , COX7C , COX8A and COX8C [ 211–213 ]. It is generally thought that assembly of complex IV occurs in a modular fashion ( Figure 5 ) [ 210 , 214 , 215 ], with the three mt-DNA encoded acting as platforms for assembly of nDNA encoded subunits into modules.…”

Section: Complex IV Assemblymentioning

confidence: 99%

Blackout in the powerhouse: clinical phenotypes associated with defects in the assembly of OXPHOS complexes and the mitoribosome

Hock

Robinson

Stroud

2020

Biochemical Journal

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Mitochondria produce the bulk of the energy used by almost all eukaryotic cells through oxidative phosphorylation (OXPHOS) which occurs on the four complexes of the respiratory chain and the F1–F0 ATPase. Mitochondrial diseases are a heterogenous group of conditions affecting OXPHOS, either directly through mutation of genes encoding subunits of OXPHOS complexes, or indirectly through mutations in genes encoding proteins supporting this process. These include proteins that promote assembly of the OXPHOS complexes, the post-translational modification of subunits, insertion of cofactors or indeed subunit synthesis. The latter is important for all 13 of the proteins encoded by human mitochondrial DNA, which are synthesised on mitochondrial ribosomes. Together the five OXPHOS complexes and the mitochondrial ribosome are comprised of more than 160 subunits and many more proteins support their biogenesis. Mutations in both nuclear and mitochondrial genes encoding these proteins have been reported to cause mitochondrial disease, many leading to defective complex assembly with the severity of the assembly defect reflecting the severity of the disease. This review aims to act as an interface between the clinical and basic research underpinning our knowledge of OXPHOS complex and ribosome assembly, and the dysfunction of this process in mitochondrial disease.

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“…High-resolution structures of the OXPHOS complexes have been critical to our understanding of their function in respiration, however, these structures also proved a valuable resource for researchers interested in the mechanisms of OXPHOS complex assembly and how defective OXPHOS might lead to disease. Our laboratory has benefitted immensely from the work of structural biologists, as we have found the mapping of massspectrometry derived data onto the 3D structures of OXPHOS complexes helpful for understanding the roles of specific subunits and assembly factors [17][18][19][20][21][22][23]. Complete high-resolution structures now exist for four of the five OXPHOS complexes, as well as multiple variations of the respiratory chain supercomplex.…”

Section: Introductionmentioning

confidence: 99%

The road to the structure of the mitochondrial respiratory chain supercomplex

Caruana

Stroud

2020

Biochemical Society Transactions

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The four complexes of the mitochondrial respiratory chain are critical for ATP production in most eukaryotic cells. Structural characterisation of these complexes has been critical for understanding the mechanisms underpinning their function. The three proton-pumping complexes, Complexes I, III and IV associate to form stable supercomplexes or respirasomes, the most abundant form containing 80 subunits in mammals. Multiple functions have been proposed for the supercomplexes, including enhancing the diffusion of electron carriers, providing stability for the complexes and protection against reactive oxygen species. Although high-resolution structures for Complexes III and IV were determined by X-ray crystallography in the 1990s, the size of Complex I and the supercomplexes necessitated advances in sample preparation and the development of cryo-electron microscopy techniques. We now enjoy structures for these beautiful complexes isolated from multiple organisms and in multiple states and together they provide important insights into respiratory chain function and the role of the supercomplex. While we as non-structural biologists use these structures for interpreting our own functional data, we need to remind ourselves that they stand on the shoulders of a large body of previous structural studies, many of which are still appropriate for use in understanding our results. In this mini-review, we discuss the history of respiratory chain structural biology studies leading to the structures of the mammalian supercomplexes and beyond.

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HIGD2A is required for assembly of the COX3 module of human mitochondrial complex IV

Cited by 14 publications

References 74 publications

Mitochondrial disorders of the OXPHOS system

Mitochondrial disorders of the OXPHOS system

Blackout in the powerhouse: clinical phenotypes associated with defects in the assembly of OXPHOS complexes and the mitoribosome

The road to the structure of the mitochondrial respiratory chain supercomplex

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